Descriptor: "MESH: Homozygote" - Searchworks@Jio Institute Digital Library Search Results

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94 results on '"MESH: Homozygote"'

1. A Homozygous Missense Variant in Hedgehog Acyltransferase (HHAT) Gene Associated with 46,XY Gonadal Dysgenesis

Author: Inas, Mazen, Alaa, Kamel, Kenneth, McElreavey, Anu, Bashamboo, Aya, Elaidy, Mohamed S, Abdel-Hamid, National Research Centre - NRC (EGYPT), Génétique du Développement humain - Human developmental genetics, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Exome sequencing, MESH: Mutation, Missense, MESH: Humans, MESH: Mutation, [SDV]Life Sciences [q-bio], XY DSD, Missense variant, MESH: Hedgehog Proteins, MESH: Gonadal Dysgenesis, 46,XY, MESH: Acyltransferases, MESH: Phenotype, Hedgehog acyltransferase, MESH: Female, Egyptian patient, MESH: Homozygote
Abstract: International audience; Introduction: Disorders of gonadal development represent a clinically and genetically heterogeneous group of DSD, and the etiology in many cases remains unknown, indicating that our knowledge of factors controlling sex determination is still limited. Methods: We describe a 46,XY DSD patient from Egypt. The patient was reared as female, born to consanguineous parents, and was referred to us at the age of 5 years because of ambiguous genitalia. On examination, the girl was microcephalic (head circumference –3 SD), but her height and weight were normal for her age and sex. Results: Exome sequencing identified a homozygous variant in the hedgehog acyltransferase (HHAT) gene, which encodes an enzyme that is required for multimerization and signaling potency of the hedgehog secreted proteins. The variant is a novel homozygous missense change c.1329C>A (p.N443K), located within transmembrane domain 9, which segregated with the phenotype in the family. Discussion/Conclusion: Our results expand the phenotypic spectrum associated with HHAT variants to include 46,XY gonadal dysgenesis and reinforce the role of exome sequencing in unraveling new genes that play a pivotal role in sexual development.
Published: 2023

2. Maize In Planta Haploid Inducer Lines: A Cornerstone for Doubled Haploid Technology

Author: Nathanaël M. A. Jacquier, Peter M. Rogowsky, Jean-Pierre Martinant, Thomas Widiez, Laurine M. Gilles, Reproduction et développement des plantes (RDP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Limagrain Europe, ANR-19-CE20-0012,NOT-LIKE-DAD,Gynogenèse in vivo chez le maïs : nouvelles connaissances sur la double fécondation chez les plantes(2019), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: MESH: Gene Editing, MESH: Genome, Plant, 0106 biological sciences, Haploid inducer line, MESH: Zea mays, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, MESH: Phenotype, 01 natural sciences, Genome, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Double fertilization, Gynogenesis, MESH: Hybrid Vigor, 03 medical and health sciences, Meiosis, Inbred strain, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Haploid, Seed development, MESH: Chromosomes, Plant, MESH: Models, Genetic, MESH: Diploidy, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, 2. Zero hunger, Genetics, 0303 health sciences, MESH: Molecular Biology, fungi, Chromosome, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Haploidy, MESH: Crops, Agricultural, MESH: Crosses, Genetic, Maize, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Transformation (genetics), MESH: Plant Breeding, MESH: Seeds, Embryo, Doubled haploidy, Ploidy, MESH: Homozygote, 010606 plant biology & botany
Abstract: International audience; Doubled haploid (DH) technology produces strictly homozygous fertile plant thanks to doubling the chromosomes of a haploid embryo/seedling. Haploid embryos are derived from either male or female germ line cells and hold only half the number of chromosomes found in somatic plant tissues, albeit in a recombinant form due to meiotic genetic shuffling. DH production allows to rapidly fix these recombinant haploid genomes in the form of perfectly homozygous plants (inbred lines), which are produced in two rather than six or more generations. Thus, DH breeding enables fast evaluation of phenotypic traits on homogenous progeny. While for most crops haploid embryos are produced by costly and often genotype-dependent in vitro methods, for maize, two unique in planta systems are available to induce haploid embryos directly in the seed. Two "haploid inducer lines", identified from spontaneous maize mutants, are able to induce embryos of paternal or maternal origin. Although effortless crosses with lines of interest are sufficient to trigger haploid embryos, substantial improvements were necessary to bring DH technology to large scale production. They include the development of modern haploid inducer lines with high induction rates (8-12%), and methods to sort kernels with haploid embryos from the normal ones. Chromosome doubling represents also a crucial step in the DH process. Recent identification of genomic loci involved in spontaneous doubling opens up perspectives for a fully in planta DH pipeline in maize. Although discovered more than 60 years ago, maize haploid inducer lines still make headlines thanks to novel applications and findings. Indeed, maternal haploid induction was elegantly diverted to deliver genome editing machinery in germplasm recalcitrant to transformation techniques. The recent discovery of two molecular players controlling haploid induction allowed to revisit the mechanistic basis of maize maternal haploid induction and to successfully translate haploid induction ability to other crops.
Published: 2021

3. Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Author: Laurent Abel, Laurie H. Glimcher, Lluis Quintana-Murci, Nico Marr, Fatima Al Ali, Jean Marc Doisne, David Langlais, Jacinta Bustamante, Marc Weisshaar, Jing Han, Jamila El Baghdadi, Frédéric Batteux, Manon Roynard, Yichao Shen, Mathieu Bourgey, Flore Rozenberg, Federica Sallusto, Peng Zhang, David Jarrossay, Carmen Oleaga-Quintas, Jean-Laurent Casanova, Daniela Latorre, Gaspard Kerner, Mahbuba Rahman, Houda Elarabi, Federico Mele, Yoann Seeleuthner, James P. Di Santo, Stuart G. Tangye, Michael S. Kobor, Janet Markle, Dusan Bogunovic, Stéphanie Boisson-Dupuis, Julia L. Maclsaac, Lucas T. Husquin, Lisa Worley, Conor Gruber, Cindy S. Ma, Jérémie Rosain, Taushif Khan, Thomas L. Carroll, Mohamed Jeljeli, Abderrahmane Errami, Anne Puel, Qiang Pan-Hammarström, Philippe Gros, Ibithal Benhsaien, Aziz Bousfiha, Fatima Ailal, Carys A. Croft, Rui Yang, Masato Ogishi, Rockefeller University [New York], Università della Svizzera italiana = University of Italian Switzerland (USI), Garvan Institute of medical research, McGill University = Université McGill [Montréal, Canada], Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Hassan II [Casablanca] (UH2MC), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Icahn School of Medicine at Mount Sinai [New York] (MSSM), We thank the patients and families, members of the laboratory, Cecilia Lindestam Arlehamn and Alessandro Sette, NIH Tetramer Core Facility (NTCF), James McCluskey, Jamie Rossjohn, and David Fairlie, the Genomics and the Flow Cytometry Resource Center of Rockefeller University, National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001866 to Rockefeller University), Steven Elledge, National Institute of Allergy and Infectious Diseases (R37AI095983 to J.L.C. and U19AI118626 to F.S.), Sackler Center for Biomedicine and Nutrition at the Center for Clinical and Translational Science (CCTS), Shapiro-Silverberg Fund for the Advancement of Translational Research at CCTS, Rockefeller University (to R.Y.), Research Grant Program of the Immune Deficiency Foundation (to R.Y.), Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), French National Research Agency under the 'Investments for the future' program (ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17-0005-01 to J.B.), ANR-LTh-MSMD-CMCD (ANR-18-CE93-0008-01 to A.P and F.S.), Fonds de Recherche en Santé Respiratoire (SRC2017 to J.B.), French Foundation for Medical Research (FRM) (EQU201903007798), the SCOR Corporate Foundation for Science, ECOS Nord (C19S01-63407 to J.B.), Swiss National Science Foundation (310030L_182728 to F.S.), French Foundation for Medical Research (FRM) (EQU201903007798), Helmut Horten Foundation, Canadian Center for Computational Genomics (C3G), Genomics Technology Platform (GTP), and Genome Canada. J. R. was supported by INSERM Poste d’accueil and and Imagine Institute, T.K. by Qatar National Research Fund (PPM1-1220-150017). S.G.T. by Program grant (1113904), Principal Research Fellowship (1042925), and Leadership 3 Investigator grant (1176665) from the National Health and Medical Research Council of Australia, C.S.M. by an Early/Mid-Career Development Research Fellowship, Ministry of Health, NSW Government, R.Y. by Stony Wold-Herbert Fund., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-18-CE93-0008,LTh-MSMD-CMCD,Différenciation des lymphocytes T-helper (Th) dans les défauts génétiques de l'immunité contre Mycobacterium et/ou Candida species.(2018), Garvan Institute of Medical Research [Darlinghurst, Australia], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)
Subjects: Male, inborn errors of immunity, [SDV]Life Sciences [q-bio], Mendelian susceptibility to mycobacterial disease, MESH: Amino Acid Sequence, Adaptive Immunity, MESH: Base Sequence, Epigenesis, Genetic, mycobacterium, MESH: INDEL Mutation, 0302 clinical medicine, MESH: DNA Methylation, INDEL Mutation, Loss of Function Mutation, Interferon gamma, MESH: Epigenesis, Genetic, MESH: CpG Islands, IFN-γ, Immunodeficiency, 0303 health sciences, biology, MESH: Dendritic Cells, Homozygote, T-Lymphocytes, Helper-Inducer, MESH: Infant, Chromatin, Pedigree, 3. Good health, Killer Cells, Natural, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, medicine.drug, MESH: Homozygote, MESH: Killer Cells, Natural, MESH: Pedigree, MESH: T-Box Domain Proteins, MESH: Interferon-gamma, T-bet, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Chromatin, Interferon-gamma, 03 medical and health sciences, Immunity, medicine, MESH: Mycobacterium, Humans, Cell Lineage, Amino Acid Sequence, MESH: Mycobacterium Infections, MESH: T-Lymphocytes, Helper-Inducer, Transcription factor, 030304 developmental biology, Mycobacterium Infections, MESH: Humans, Base Sequence, MESH: Transcriptome, MESH: Child, Preschool, Infant, MESH: Loss of Function Mutation, Dendritic Cells, DNA Methylation, Mycobacterial disease, MESH: Cell Lineage, medicine.disease, biology.organism_classification, Immunity, Innate, MESH: Male, innate-like adaptive lymphocyte, Mycobacterial antigen, Immunology, CpG Islands, innate lymphocyte, T-Box Domain Proteins, Transcriptome, immunodeficiency, MESH: Female, 030217 neurology & neurosurgery, CD8, MESH: Adaptive Immunity, Mycobacterium
Abstract: International audience; Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.
Published: 2020

4. Factors that influence bidirectional long-tract homozygosis due to double-strand break repair in Candida albicans

Author: Murielle Chauvel, Adeline Feri, Corinne Maufrais, Mélanie Legrand, Christophe d'Enfert, Timea Marton, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics, Institut Pasteur [Paris] (IP), T.M. is the recipient of a Ph.D. fellowship from the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID) and Indo-French Centre for the Promotion of Advanced Research CEFIPRA (CEFIPRA). We acknowledge support from the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases [ANR10-LABX-62-IBEID]) and of the Indo-French Centre for the Promotion of Advanced Research CEFIPRA (CEFIPRA). A.F. was the recipient of a Ph.D. grant from INRA Jouy-en-Josas and Institut Pasteur., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: DNA Repair, [SDV]Life Sciences [q-bio], MESH: DNA Breaks, Double-Stranded, Loss of Heterozygosity, MESH: DNA Replication, MESH: DNA Breaks, chemistry.chemical_compound, MESH: Saccharomyces cerevisiae Proteins, 0302 clinical medicine, Mismatch Repair Pathway, Candida albicans, DNA Breaks, Double-Stranded, MESH: DNA Repair, Genetics, Gene Rearrangement, Recombination, Genetic, 0303 health sciences, Homozygote, MESH: Saccharomyces cerevisiae, MESH: Chromosomes, Fungal, Double Strand Break Repair, mitotic recombination, break induced replication, MESH: Recombination, Genetic, Chromosomes, Fungal, MESH: Homozygote, DNA Replication, MESH: Mutation, Mitotic crossover, Saccharomyces cerevisiae Proteins, MESH: Gene Rearrangement, DNA repair, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, Centromere, MESH: Diploidy, Gene, Alleles, 030304 developmental biology, MESH: Loss of Heterozygosity, Investigation, MESH: Alleles, MESH: Candida albicans, DNA Breaks, bidirectional loss-of-heterozygosity, biology.organism_classification, Diploidy, chemistry, Mutation, 030217 neurology & neurosurgery, DNA
Abstract: Genomic rearrangements have been associated with the acquisition of adaptive phenotypes, allowing organisms to efficiently generate new favorable genetic combinations. The diploid genome of Candida albicans is highly plastic, displaying numerous genomic rearrangements that are often the by-product of the repair of DNA breaks. For example, DNA double-strand breaks (DSB) repair using homologous-recombination pathways are a major source of loss-of-heterozygosity (LOH), observed ubiquitously in both clinical and laboratory strains of C. albicans. Mechanisms such as break-induced replication (BIR) or mitotic crossover (MCO) can result in long tracts of LOH, spanning hundreds of kilobases until the telomere. Analysis of I-SceI-induced BIR/MCO tracts in C. albicans revealed that the homozygosis tracts can ascend several kilobases towards the centromere, displaying homozygosis from the break site towards the centromere. We sought to investigate the molecular mechanisms that could contribute to this phenotype by characterizing a series of C. albicans DNA repair mutants, including pol32-/-, msh2-/-, mph1-/- and mus81-/-. The impact of deleting these genes on genome stability revealed functional differences between Saccharomyces cerevisiae (a model DNA repair organism) and C. albicans. Additionally, we demonstrated that ascending LOH tracts towards the centromere are associated with intrinsic features of BIR and potentially involve the mismatch repair pathway which acts upon natural heterozygous positions. Overall, this mechanistic approach to study LOH deepens our limited characterization of DNA repair pathways in C. albicans and brings forth the notion that centromere proximal alleles from DNA break sites are not guarded from undergoing LOH.
Published: 2020

5. Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Author: Lluis Quintana-Murci, Antoine Favier, Franck Rapaport, David Neil Cooper, Peter D. Stenson, Etienne Patin, Laurent Abel, Jean-Laurent Casanova, Yufei Luo, Marie Lopez, Antonio Rausell, Yoann Seeleuthner, The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK, Howard Hughes Medical Institute (HHMI), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), The Laboratory of Clinical Bioinformatics was supported by the French National Research Agency (ANR)'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01) and Christian Dior Couture, Dior. The Laboratory of Human Geneticsof Infectious Diseases was supported, in part, by grants from ANR under the'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01), the Fondation pourla Recherche Médicale (Equipe FRM EQU201903007798), the St. Giles Foundation,and the Rockefeller University. The laboratory of L.Q.-M. is supported by theInstitut Pasteur, the Collège de France, the French Government’s Investissementsd’Avenir program, Laboratoires d’Excellence'Integrative Biology of Emerging Infectious Diseases'(Grant ANR-10-LABX-62-IBEID) and'Milieu Intérieur'(GrantANR-10-LABX-69-22701), and the Fondation pour la Recherche Médicale (EquipeFRM DEQ20180339214). D.N.C. and P.D.S. acknowledge the financial supportof Qiagen Inc. through a license agreement with Cardiff University., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cardiff University, Collège de France - Chaire Génomique humaine et évolution, PATIN, Etienne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: Linkage disequilibrium, Pseudogene, Population, MESH: Human Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, 03 medical and health sciences, Negative selection, 0302 clinical medicine, MESH: Fucosyltransferases, Loss of Function Mutation, positive selection, Apolipoproteins L, Humans, MESH: Proteins, MESH: Genetic Variation, Allele, education, Gene, Loss function, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Sex Chromosomes, MESH: Humans, redundancy, MESH: Alleles, MESH: Apolipoproteins L, Homozygote, Genetic Variation, Proteins, negative selection, MESH: Sex Chromosomes, Human Genetics, MESH: Loss of Function Mutation, Biological Sciences, Fucosyltransferases, Phenotype, loss of function, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human genome, pseudogenization, 030217 neurology & neurosurgery, MESH: Homozygote
Abstract: Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the knownFUT2mutant allele conferring resistance to intestinal viruses and anAPOL3variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival.Significance statementHuman genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.
Published: 2020

6. ATP6V1B1 recurrent mutations in Algerian deaf patients associated with renal tubular acidosis

Author: Crystel Bonnet, Sonia Talbi, Christine Petit, Fatima Ammar-Khodja, Merieme Djebbar, Farid Boudjenah, Malika Dahmani, Sofiane Ouhab, Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Établissement Public Hospitalier Bachir Mentouri, Service ORL [Tizi Ouzou], Centre Hospitalier Universitaire Mohamed Nedir, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), We are grateful to the family members for their participation in this study. The study was supported by National Veterinary School and the Algerian Ministry of Higher Education and Scientific research., Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Male, MESH: Acidosis, Renal Tubular, MESH: Introns, [SDV]Life Sciences [q-bio], Gene mutation, Gastroenterology, Renal tubular acidosis, Sensorineural hearing loss (SNHL), 0302 clinical medicine, Distal renal tubular acidosis, 030223 otorhinolaryngology, Frameshift Mutation, education.field_of_study, Enlarged vestibular aqueduct (EVA), MESH: Vestibular Aqueduct, Homozygote, MESH: Frameshift Mutation, General Medicine, Acidosis, Renal Tubular, Exons, MESH: Infant, 3. Good health, Child, Preschool, Sensorineural hearing loss, Female, MESH: Algeria, MESH: Homozygote, medicine.medical_specialty, Vacuolar Proton-Translocating ATPases, Distal renal tubular acidosis (dRTA), Hearing Loss, Sensorineural, Population, MESH: Vacuolar Proton-Translocating ATPases, Frameshift mutation, Vestibular Aqueduct, 03 medical and health sciences, 030225 pediatrics, Internal medicine, medicine, otorhinolaryngologic diseases, Humans, education, ATP6V1B1, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, Metabolic acidosis, medicine.disease, Introns, MESH: Male, Otorhinolaryngology, MESH: Hearing Loss, Sensorineural, Algeria, Pediatrics, Perinatology and Child Health, business, MESH: Exons, MESH: Female, Enlarged vestibular aqueduct
Abstract: International audience; Hereditary distal renal tubular acidosis (dRTA) is a rare disorder characterized by metabolic acidosis due to impaired renal acid excretion. To date, three genes (ATP6V1B1, ATP6V0A4 and SLC4A1) have been reported to be responsible for this genetic disorder. Notably, mutations of ATP6V1B1 gene, which encode B1-subunit of H + -ATPase pump cause distal renal tubular acidosis often, associated with sensorineural hearing loss (SNHL). Furthermore, enlarged vestibular aqueduct (EVA) was also described in some patients with ATP6V1B1 mutations. Four Algerian unrelated patients presented with dRTA and SNHL were recruited. The ATP6V1B1 gene was preferentially analyzed in all these patients by Sanger sequencing. We identified two previously reported variants in ATP6V1B1 gene: a frameshift mutation (c.1155dupC: p.(Ile386Hisfs*56) in exon 12 and a splicing mutation in intron 2 (c.175-1G > C: p?). Both mutations were homozygous in affected members. Interestingly, one patient with p.(Ile386Hisfs*56) mutation presented profound SNHL and bilateral enlarged vestibular aqueduct (EVA). Our study indicates the importance contribution of ATP6V1B1 gene mutations to the pathogenesis of the dRTA in the Algerian population and will contribute to introducing principles to predict the characteristics of the dRTA in patients. Thus, screening for this gene could allow rapid patient management and provide adequate genetic counseling.
Published: 2020

7. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms: New insights in homozygous GRN mutations

Author: Huin, Vincent, Barbier, Mathieu, Bottani, Armand, Lobrinus, Johannes, Clot, Fabienne, Lamari, Foudil, Chat, Laureen, Rucheton, Benoît, Fluchère, Frédérique, Auvin, Stéphane, Myers, Peter, Gelot, Antoinette, Camuzat, Agnès, Caillaud, Catherine, Jornéa, Ludmila, Forlani, Sylvie, Saracino, Dario, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, HUIN, Vincent, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], and Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A)
Subjects: MESH: Epilepsy / genetics, TDP-43, MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging, MESH: TDP-43 Proteinopathies / physiopathology, MESH: RNA Splicing / genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Child, MESH: Cerebellar Ataxia / genetics, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cerebellar ataxia, MESH: Heterozygote, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Middle Aged, Neuronal ceroid lipofuscinosis, MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology, MESH: Parkinsonian Disorders / genetics, frontotemporal lobar degeneration, MESH: Cognitive Dysfunction / genetics, MESH: Young Adult, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Parkinsonian Disorders / diagnostic imaging, MESH: TDP-43 Proteinopathies / genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Neuronal Ceroid-Lipofuscinoses / genetics, GRN, Frontotemporal dementia, MESH: Homozygote, MESH: Progranulins / metabolism, MESH: Rare Diseases, Progranulin, MESH: Mutation, MESH: Frontotemporal Dementia / genetics, MESH: Age of Onset, MESH: Parkinsonian Disorders / physiopathology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Frontotemporal Dementia / diagnostic imaging, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Retinitis Pigmentosa / genetics, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Adolescent, MESH: Humans, MESH: Progranulins / genetics, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: TDP-43 Proteinopathies / diagnostic imaging, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Frontotemporal Dementia / physiopathology, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counseling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Published: 2020

8. Next-generation sequencing and recombinant expression characterized aberrant splicing mechanisms and provided correction strategies in factor VII deficiency

Author: Delphine Buthiau, Paolo Ferraresi, Dario Balestra, Caroline Guittard, Roula Farah, Mirko Pinotti, Iva Maestri, Brigitte Pan-Petesh, Muriel Giansily-Blaizot, Università degli Studi di Ferrara (UniFE), Département Hématologie biologique [CHRU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Saint George Hospital University Medical Center [Beirut, Lebanon]
Subjects: MESH: Mutation, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Factor VII Deficiency, RNA Splicing, 030204 cardiovascular system & hematology, Biology, Deep-intronic Mutation, Disorders of Coagulation and Fibrinolysis, FVII Deficiency, New Generation Sequencing, Splicing Correction, Article, DNA sequencing, NO, New Generation Sequencing, 03 medical and health sciences, Exon, chemistry.chemical_compound, 0302 clinical medicine, Humans, Allele, MESH: High-Throughput Nucleotide Sequencing, Gene, 030304 developmental biology, Genetics, 0303 health sciences, MESH: Humans, Factor VII, Homozygote, Haplotype, Coagulation & its Disorders, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Exons, Hematology, FVII Deficiency, Splicing Correction, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, chemistry, MESH: Factor VII Deficiency, Deep-intronic Mutation, Mutation, RNA splicing, MESH: Factor VII, Disorders of Coagulation and Fibrinolysis, MESH: Exons, MESH: RNA Splicing, MESH: Homozygote, Minigene
Abstract: International audience; Despite the exhaustive screening of F7 gene exons and exon-intron boundaries and promoter region, a significant proportion of mutated alleles remains unidentified in patients with coagulation factor VII deficiency. Here, we applied next-generation sequencing to 13 FVII-deficient patients displaying genotype-phenotype discrepancies upon conventional sequencing, and identified six rare intronic variants. Computational analysis predicted splicing effects for three of them, which would strengthen (c.571+78G>A; c.806-329G>A) or create (c.572-392C>G) intronic 5' splice sites (5'ss). In F7 minigene assays, the c.806-329G>A was ineffective while the c.571+78G>A change led to usage of the +79 cryptic 5'ss with only trace levels of correct transcripts (3% of wild-type), in accordance with factor VII activity levels in homozygotes (1-3% of normal). The c.572-392C>G change led to pseudo-exonization and frame-shift, but also substantial levels of correct transcripts (approx. 70%). However, this variant was associated with the common F7 polymorphic haplotype, predicted to further decrease factor VII levels; this provided some kind of explanation for the 10% factor VII levels in the homozygous patient. Intriguingly, the effect of the c.571+78G>A and c.572-392C>G changes, and particularly of the former (the most severe and well-represented in our cohort), was counteracted by antisense U7snRNA variants targeting the intronic 5'ss, thus demonstrating their pathogenic role. In conclusion, the combination of next-generation sequencing of the entire F7 gene with the minigene expression studies elucidated the molecular bases of factor VII deficiency in 10 of 13 patients, thus improving diagnosis and genetic counseling. It also provided a potential therapeutic approach based on antisense molecules that has been successfully exploited in other disorders.
Published: 2020

9. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms

Author: HUIN, Vincent, Barbier, Mathieu, Bottani, Armand, Lobrinus, Johannes, Clot, Fabienne, Lamari, Foudil, Chat, Laureen, Rucheton, Benoît, Fluchère, Frédérique, Auvin, Stéphane, Myers, Peter, Gelot, Antoinette, Camuzat, Agnès, Caillaud, Catherine, Jornéa, Ludmila, Forlani, Sylvie, Saracino, Dario, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), and Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié - Salpêtrière, Paris, France
Subjects: MESH: Rare Diseases, Progranulin, MESH: Mutation, MESH: Epilepsy / genetics, MESH: Frontotemporal Dementia / genetics, TDP-43, MESH: Age of Onset, MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging, MESH: Parkinsonian Disorders / physiopathology, MESH: TDP-43 Proteinopathies / physiopathology, MESH: RNA Splicing / genetics, MESH: Frontotemporal Dementia / diagnostic imaging, MESH: Child, MESH: Cerebellar Ataxia / genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Retinitis Pigmentosa / genetics, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cerebellar ataxia, MESH: Heterozygote, MESH: Adolescent, MESH: Humans, MESH: Middle Aged, MESH: Progranulins / genetics, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: TDP-43 Proteinopathies / diagnostic imaging, MESH: Male, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Neuronal ceroid lipofuscinosis, MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology, MESH: Parkinsonian Disorders / genetics, frontotemporal lobar degeneration, MESH: Cognitive Dysfunction / genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, MESH: Parkinsonian Disorders / diagnostic imaging, MESH: TDP-43 Proteinopathies / genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Frontotemporal Dementia / physiopathology, MESH: Neuronal Ceroid-Lipofuscinoses / genetics, MESH: Female, Frontotemporal dementia, GRN, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Homozygote, MESH: Progranulins / metabolism
Abstract: International audience; Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counseling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Published: 2020

10. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

11. The spectrum of GJB2 gene mutations in Algerian families with nonsyndromic hearing loss from Sahara and Kabylie regions

Author: Crystel Bonnet, Sonia Talbi, Christine Petit, Mohammed Tahar Mansouri, Farid Boudjenah, Fatima Ammar Khodja, Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Sidi Belloua, Hôpital de Frantz fanon, Centre hospitalo-universitaire de Bab El Oued, Institut Pasteur [Paris] (IP), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the Algerian Ministry of Higher Education and Scientific Research., We wish to thank the family members for their kind cooperation in this study. We are grateful to directors of deafness school, Arouini El Hachemie (Ghardaia school), Nezali Nadia and Aicha (Bejaia school), Akache Said (Tizi-Ouzou school), Mays Naima and Hadjemi Naima (Boumerdes school), Sabane Ali and Kacimi El Hassani Anissa (Bouira School), Dr Hadad (Baraki School), team of EHS Hospital of El Oued and Dr Lounis Abd Aziz (Service Ortorhyngologie (ORL), hôpital Frantz Fanon, Bejaia) for their help in sample collection., Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], and Chaire Génétique et physiologie cellulaire
Subjects: Male, [SDV]Life Sciences [q-bio], Deafness, Compound heterozygosity, medicine.disease_cause, Connexins, Cohort Studies, Gjb2 gene, Exon, MESH: Child, Prevalence, Child, MESH: Cohort Studies, Genetics, 0303 health sciences, Mutation, MESH: Middle Aged, biology, Homozygote, 030305 genetics & heredity, Exons, General Medicine, Middle Aged, MESH: Infant, 3. Good health, GJB2, Connexin 26, MESH: Young Adult, Child, Preschool, c.35delG, Female, Isolated Deafness, medicine.symptom, MESH: Algeria, GJB6, MESH: Homozygote, Adult, MESH: Mutation, Adolescent, Hearing loss, Black People, MESH: Deafness, MESH: Connexin 30, Young Adult, 03 medical and health sciences, Connexin 30, medicine, otorhinolaryngologic diseases, Humans, Prelingual deafness, MESH: Prevalence, 030304 developmental biology, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, MESH: Adult, MESH: Male, MESH: Connexins, Otorhinolaryngology, Algeria, Pediatrics, Perinatology and Child Health, biology.protein, MESH: African Continental Ancestry Group, business, MESH: Exons, MESH: Female
Abstract: International audience; Introduction: DFNB1, caused by mutations of GJB2 or GJB6, is the most prevalent genetic form of nonsyndromic (i.e., isolated) congenital deafness in countries located around the Mediterranean Sea. Because some mutations are restricted to specific ethnic-geographic groups, we studied the prevalence and spectrum of GJB2/GJB6 mutations in deaf patients originating from two different Algerian regions, Kabylie and Sahara.Patients and methods: Among 91 reportedly unrelated Algerian patients affected by prelingual deafness, 80 patients (41 from Kabylie and 39 from Sahara) were diagnosed with isolated deafness. All had profound deafness, except one patient with mild deafness. They were screened for the presence of GJB2 mutations by direct sequencing of the single coding exon of GJB2. Patients without mutations were then screened for the presence of the most frequent two deletions of GJB6: del(GJB6-D13S1854) and del(GJB6-D13S1830).Results: Causative mutations were found in 13 and 8 patients from Kabylie and Sahara, respectively, accounting for more than a quarter of the cohort. The c.35delG, p.Gly12Valfs*2 mutation remains the most important mutation both in Kabylie (10 patients) and Sahara (7 patients). All detected patients were homozygous for this mutation. In addition, two other mutations (c.139G > T, p.Glu47* and c.167delT, p.Leu56Argfs*26) were found homozygous in one family each, and two patients were compound heterozygotes for (c.35delG p.Gly12Valfs*2/c.139G > T, p.Glu47*). No deletion of GJB6 was detected.Conclusion: We confirm that mutations in GJB2, mainly c.35delG, are one of the most prevalent causes of nonsyndromic congenital deafness in Algeria, whereas the del (GJB6-D13S1854) and del (GJB6-D13S1830) deletions of GJB6 contribute little, if any. Further investigation is needed to identify the cause of deafness in other patients without diagnostic.
Published: 2019

12. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms: New insights in homozygous GRN mutations

Author: Antoinette Gelot, Alexis Brice, Agnès Camuzat, Benoit Rucheton, Laureen Chat, Dario Saracino, Frédérique Fluchère, Johannes Alexander Lobrinus, Fabienne Clot, Sylvie Forlani, Peter Myers, Alexandra Durr, Ludmila Jornea, Isabelle Le Ber, Vincent Huin, Foudil Lamari, Mathieu Barbier, Armand Bottani, Catherine Caillaud, Stéphane Auvin, Charles Duyckaerts, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Technocentre Renault [Guyancourt], RENAULT, Génétique médicale, Hôpitaux Universitaires de Genève (HUG), University of Geneva [Switzerland], Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Bordeaux (UB), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Polytech'Paris-UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié - Salpêtrière, Paris, France, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, MESH: Epilepsy / genetics, MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging, MESH: TDP-43 Proteinopathies / physiopathology, MESH: RNA Splicing / genetics, ddc:616.07, 0302 clinical medicine, MESH: Child, MESH: Cerebellar Ataxia / genetics, ddc:576.5, Age of Onset, Child, ComputingMilieux_MISCELLANEOUS, Mutation, MESH: Middle Aged, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Neuronal ceroid lipofuscinosis, MESH: Parkinsonian Disorders / genetics, MESH: Cognitive Dysfunction / genetics, MESH: Young Adult, Frontotemporal Dementia, GRN, Retinitis Pigmentosa, MESH: Progranulins / metabolism, MESH: Rare Diseases, MESH: Frontotemporal Dementia / genetics, Cerebellar Ataxia, MESH: Age of Onset, RNA Splicing, 03 medical and health sciences, Parkinsonian Disorders, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retinitis pigmentosa, Humans, Cognitive Dysfunction, MESH: Adolescent, MESH: Humans, Epilepsy, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: TDP-43 Proteinopathies / diagnostic imaging, 030104 developmental biology, FOS: Biological sciences, Neurology (clinical), MESH: Frontotemporal Dementia / physiopathology, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, TDP-43, medicine.disease_cause, Progranulins, MESH: Heterozygote, Genetics, Homozygote, Frontotemporal lobar degeneration, Middle Aged, MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology, frontotemporal lobar degeneration, Neurons and Cognition (q-bio.NC), MESH: Parkinsonian Disorders / diagnostic imaging, MESH: TDP-43 Proteinopathies / genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, MESH: Neuronal Ceroid-Lipofuscinoses / genetics, Frontotemporal dementia, MESH: Homozygote, Adult, Progranulin, Heterozygote, MESH: Mutation, Adolescent, MESH: Parkinsonian Disorders / physiopathology, Biology, MESH: Frontotemporal Dementia / diagnostic imaging, Young Adult, Rare Diseases, Neuronal Ceroid-Lipofuscinoses, MESH: Retinitis Pigmentosa / genetics, medicine, Dementia, Quantitative Biology - Genomics, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Genomics (q-bio.GN), Cerebellar ataxia, MESH: Progranulins / genetics, Biomolecules (q-bio.BM), MESH: Male, Quantitative Biology - Biomolecules, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Quantitative Biology - Neurons and Cognition, TDP-43 Proteinopathies, Age of onset, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Published: 2019

13. Identification of a homozygous GFPT2 variant in a family with asthenozoospermia

Author: Mehdi Totonchi, Masomeh Askari, Dor Mohammad Kordi-Tamandani, Ken McElreavey, Navid Almadani, University of Sistan and Baluchestan [Iran], Royan Institute for Reproductive Biomedicine [Tehran, Iran], Academic Center for Education, Culture and Research (ACECR), Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP), and The present study was supported in part by a grant from the University of Sistan and Bluchestan (USB), Zahedan, Iran, a grant from the Royan Research Institute, Tehran, Iran and a grant from the Iran National Science Foundation (INSF).
Subjects: Male, 0301 basic medicine, MESH: Amino Acid Sequence, Iran, Gene mutation, medicine.disease_cause, 0302 clinical medicine, Sperm motility, Exome sequencing, Genetics, Mutation, Homozygote, MESH: Spermatozoa, MESH: Reactive Oxygen Species, General Medicine, MESH: Sperm Motility, Spermatozoa, Phenotype, MESH: Case-Control Studies, Pedigree, Asthenozoospermia, 030220 oncology & carcinogenesis, Whole-exome sequencing, Sperm Motility, MESH: Homozygote, endocrine system, MESH: Mutation, MESH: Pedigree, MESH: Sequence Alignment, Semen, Biology, MESH: Infertility, Male, 03 medical and health sciences, MESH: Whole Exome Sequencing, Exome Sequencing, MESH: Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), medicine, Humans, Amino Acid Sequence, Gene, MESH: Semen, Infertility, Male, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), MESH: Humans, urogenital system, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Male, MESH: Asthenozoospermia, GFPT2, 030104 developmental biology, Case-Control Studies, MESH: Iran, Reactive oxygen species, Sequence Alignment
Abstract: Purpose Asthenozoospermia (ASZ) is a condition characterized by reduced sperm motility in semen affecting approximately 19% of infertile men. Major risk factors, particularly gene mutations, still remain unknown. The main aim of the present study was to identify novel genes and mutations that may influence human sperm motility. Methods Whole-exome sequencing (WES) was performed on a large pedigree of infertile men (n = 5) followed by bioinformatics analyses. Candidate pathogenic variants were screened in a control cohort of 400 ancestry-matched Iranian fertile men, 30 unrelated men with idiopathic ASZ, and public databases. Results A rare mutation in GFPT2 gene (c.1097G > A; p.Arg366Gln) located in the SIS 1 domain was segregated with the phenotype and was consistent with autosomal recessive inheritance. The in silico analyses revealed that the mutation might affect the function of SIS 1 domain and abolish its carbohydrate-binding ability. Conclusion Homozygosity of the GFPT2 p.Arg366Gln mutation was associated with increased levels of reactive oxygen species (ROS) in spermatozoa and decreased sperm motility.
Published: 2019

14. Mutations in DNAJB13 , Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility

Author: André Coste, Catherine Faucon, Serge Amselem, Bruno Copin, Sylvie Tissier, Estelle Escudier, Sylvain Blanchon, Nathalie Collot, Emilie Bequignon, Philippe Duquesnoy, Ludovic Jeanson, Patrick Lorès, Lucie Thomas, Li Yuan, Bruno Crestani, Aminata Touré, Jean Philippe Wolf, Elma El Khouri, Benoit Vallette, Marie Legendre, Guy Montantin, Gérard Gacon, Florence Dastot-Le Moal, Emmanuel Dulioust, Catherine Patrat, Jean Francois Papon, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Chinese Academy of Sciences [Beijing] (UCAS), CHI Créteil, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Couvet, Sandrine
Subjects: 0301 basic medicine, Male, Axoneme, [SDV]Life Sciences [q-bio], MESH: Heat-Shock Proteins, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Missense mutation, Exome, Genetics(clinical), Genetics (clinical), Heat-Shock Proteins, Primary ciliary dyskinesia, Genetics, Mutation, MESH: Exome, 030219 obstetrics & reproductive medicine, DNAJB13, MESH: Middle Aged, Protein Stability, Cilium, MESH: Polymorphism, Single Nucleotide, MESH: Proteasome Endopeptidase Complex, MESH: Spermatozoa, Homozygote, Middle Aged, PCD, MESH: Axoneme, Phenotype, Spermatozoa, [SDV] Life Sciences [q-bio], central complex, Flagella, Motile cilium, Female, radial spoke, MESH: Molecular Chaperones, MESH: Homozygote, Ciliary Motility Disorders, Proteasome Endopeptidase Complex, sperm flagellum, MESH: Mutation, Adolescent, RNA Splicing, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Infertility, Male, MESH: Phenotype, MESH: Flagella, Polymorphism, Single Nucleotide, MESH: HSP40 Heat-Shock Proteins, 03 medical and health sciences, MESH: Cilia, Semen, MESH: Protein Stability, Report, medicine, Humans, Cilia, Gene, MESH: Semen, Infertility, Male, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, Sperm flagellum, MESH: Apoptosis Regulatory Proteins, Kartagener Syndrome, HSP40 Heat-Shock Proteins, medicine.disease, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Kartagener Syndrome, MESH: Ciliary Motility Disorders, MESH: RNA Splicing, Apoptosis Regulatory Proteins, MESH: Female, Molecular Chaperones
Abstract: International audience; Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ∼15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.
Published: 2016
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15. A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD

Author: Farida Jennane, Hicham Charoute, Anu Bashamboo, Joelle Bignon-Topalovic, Ken McElreavey, Abderrahim Malki, Abdelhamid Barakat, Hassan Rouba, Amina Bakhchane, Yassine Naasse, Laboratoire de Génétique Moléculaire Humaine, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté des Sciences Ben M'sik [Casablanca], Université Hassan II [Casablanca] (UH2MC), Génétique du Développement humain - Human developmental genetics, and Institut Pasteur [Paris] (IP)
Subjects: Male, 46, XX Disorders of Sex Development, Disorder of sexual development, MESH: Amino Acid Sequence, medicine.disease_cause, Keratoderma, Palmoplantar, Squamous cell carcinoma, MESH: Child, Missense mutation, Child, Receptor, Wnt Signaling Pathway, Exome sequencing, Genetics, MESH: 46, XX Disorders of Sex Development, Mutation, Homozygote, MESH: Wnt Signaling Pathway, Wnt signaling pathway, Pedigree, MESH: Young Adult, MESH: Protein Domains, Female, MESH: Homozygote, Adult, Adolescent, MESH: Pedigree, Molecular Sequence Data, Mutation, Missense, Biology, RSPO1<%2Fitalic>%22">RSPO1, MESH: Keratoderma, Palmoplantar, Young Adult, Protein Domains, medicine, Humans, Palmoplantar keratoderma, Amino Acid Sequence, MESH: Hearing Loss, Hearing Loss, RSPO1, Gene, MESH: Thrombospondins, MESH: Adolescent, MESH: Mutation, Missense, MESH: Molecular Sequence Data, MESH: Humans, MESH: Adult, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Male, Thrombospondins, MESH: Female
Abstract: International audience; R-spondin proteins are secreted agonists of canonical WNT/β-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease.
Published: 2018

16. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Author: Warren J. Leonard, Nima Rezaei, Kathryn Payne, Isabelle Meyts, Laurent Abel, Cindy S. Ma, Marianne Leruez-Ville, Janet Chou, Alain Hovnanian, Jian-Xin Lin, Simon J. Pelham, Danielle T. Avery, Matthieu Bouaziz, Bethany Pillay, Tanwir Habib, Anne Puel, Sevgi Keles, Juan Li, Isabelle Pellier, Jamel El-Benna, Bernhard Fleckenstein, Ahmet Ozen, Vivien Béziat, Ingrid Müller-Fleckenstein, Damien Chaussabel, Samaneh Zoghi, Yi Wang, Paul Gray, Matthias Titeux, Yoann Zerbib, Talal A. Chatila, Marie-Alexandra Alyanakian, Capucine Picard, Orli Wargon, Ayper Somer, Marie-Olivia Chandesris, Thibaut Leclercq, Ibtihal Benhsaien, Aziz Belkadi, Jean-Laurent Casanova, Romain Lévy, Peng Li, Geetha Rao, Ai Ing Lim, James P. Di Santo, Nico Marr, Sylvie Fraitag, Frédégonde About, Elissa K. Deenick, Bertrand Boisson, Jacinta Bustamante, Mélanie Migaud, Bodo Grimbacher, Aziz Bousfiha, Fatima Ailal, Safa Baris, Antoine Guérin, Stuart G. Tangye, Romain Guery, Ning Du, Vimel Rattina, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rockefeller University [New York], National Institutes of Health [Bethesda] (NIH), Garvan Institute of Medical Research [Darlinghurst, Australia], University of New South Wales [Sydney] (UNSW), CHU Ibn Rochd [Casablanca], Université Hassan II [Casablanca] (UH2MC), Service d'Immuno-Hémato-Oncologie Pédiatrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Universal Scientific Education and Research Network (USERN), Marmara University [Kadıköy - İstanbul], Necmettin Erbakan University [Konya, Turquie], Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Sidra Medicine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Freiburg University Medical Center, Sydney children's hospital, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Service d'immuno-hématologie pédiatrique [CHU Necker], Laboratoire de Virologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5), Centre d'étude des Déficits Immunitaires, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Istanbul University, Research Center for Immunodeficiencies [Tehran, Iran], Tehran University of Medical Sciences (TUMS), University of New South Wales [Canberra Campus] (UNSW), Howard Hughes Medical Institute [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was supported by grants from INSERM, Paris Descartes University, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID), the Jeffrey Modell Foundation Translational Research Program, the French National Research Agency (ANR, grant nos. GENCMCD-ANR-11-BSV3–005-01, HGDIFD-ANR-14-CE15-0006-01, NKIR-ANR-13-PDOC-0025-01, and EURO-CMC-ANR-14-RARE-0005-02), and grants awarded under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the National Institute of Allergy and Infectious Diseases of the NIH (grant nos. U01AI109697 and R01AI127564), the Rockefeller University, the Howard Hughes Medical Institute, the St. Giles Foundation, the Institut Pasteur, and FP7, under grant agreements 305578 (PathCO) and 317057 (HOMIN). We thank the Centre de Recherche Translationnelle (Institut Pasteur) for technical assistance. V.B. is supported by the ANR (grant no. NKIR-ANR-13-PDOC-0025-01). R.L. is supported by the INSERM Ph.D. program (Poste d’Accueil INSERM), a Fulbright grant (Franco-American commission), and a Philippe Foundation scholarship. Y.Z. received the 'médaille d’or du Centre Hospitalier Universitaire d’Amiens.' Y.W. is supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, grant no. 13318). F. About holds a fellowship from Fondation pour la Recherche Médicale (FRM, grant no. FDM20140630671). A.G. is supported by an IFNGPHOX grant (no. ANR13-ISV3-0001-01) from ANR. B.G. was funded by BMBF (German Federal Ministry of Education and Research) grants 01E01303 and 01ZX1306F. I.M. is supported by a klinische onderzoeks-en opleidingsraad (clinical research council) grant from UZ Leuven, a klinisch onderzoeksfonds (clinical research fund) grant from KU Leuven, and an International Mobility Grant from Fonds voor Wetenschappelijk Onderzoek (fund for scientific research) Vlaanderen. C.S.M., E.K.D., and S.G.T. are supported by grants and fellowships from the National Health and Medical Research Council of Australia. C.S.M., P.G., E.K.D., and S.G.T. are members of CIRCA (Clinical Immunogenomics Research Consortia Australia), which is funded by the Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, and the John Cook Brown Foundation. A.I.L. is a scholar of the Pasteur-Paris University International Ph.D. program and is supported by a Ph.D. International Training Network grant from the European Union’s Seventh Framework Program under grant agreement no. 317057 (HOMIN). T.A.C. was supported by a grant from the National Institute of Allergy and Infectious Diseases of the NIH (5R01AI065617). S.K. was supported by a grant from the Scientific and Technological Research Council of Turkey (1059B191300622). J.-X.L., P.L., N.D., and W.J.L. were supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. A.P. was supported by an AP-HP interface contract., We thank the patients and their families for participating in this study. We thank J. E. Darnell and C. Mertens for advice and for providing reagents. We thank the members of the laboratory, especially F. Jabot-Hanin and V. Pedergnana, for their valuable input on linkage analysis, L. Amar, Y. Nemirovskaya, D. Papandrea, E. Anderson, M. Woollett, C. Desvallées, C. Patissier, and M. Corrias for administrative assistance, E. Jouanguy and Y. Itan for helpful discussions, S. Boucherit for clinical data collection, S. Jacques and the Cochin genomics platform for microarray experiments, and N. Goudin and R. Desveaux of the Necker Institute Imaging Facility., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Garvan Institute of medical research, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Sydney Children's hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Beziat, Vivien, Li, Juan, Lin, Jian-Xin, Ma, Cindy S., Li, Peng, Bousfiha, Aziz, Pellier, Isabelle, Zoghi, Samaneh, Baris, Safa, Keles, Sevgi, Gray, Paul, Du, Ning, Wang, Yi, Zerbib, Yoann, Levy, Romain, Leclercq, Thibaut, About, Fredegonde, Lim, Ai Ing, Rao, Geetha, Payne, Kathryn, Pelham, Simon J., Avery, Danielle T., Deenick, Elissa K., Pillay, Bethany, Chou, Janet, Guery, Romain, Belkadi, Aziz, Guerin, Antoine, Migaud, Melanie, Rattina, Vimel, Ailal, Fatima, Benhsaien, Ibtihal, Bouaziz, Matthieu, Habib, Tanwir, Chaussabel, Damien, Marr, Nico, El-Benna, Jamel, Grimbacher, Bodo, Wargon, Orli, Bustamante, Jacinta, Boisson, Bertrand, Mueller-Fleckenstein, Ingrid, Fleckenstein, Bernhard, Chandesris, Marie-Olivia, Titeux, Matthias, Fraitag, Sylvie, Alyanakian, Marie-Alexandra, Leruez-Ville, Marianne, Picard, Capucine, Meyts, Isabelle, Di Santo, James P., Hovnanian, Alain, Somer, Ayper, Ozen, Ahmet, Rezaei, Nima, Chatila, Talal A., Abel, Laurent, Leonard, Warren J., Tangye, Stuart G., Puel, Anne, and Casanova, Jean-Laurent
Subjects: 0301 basic medicine, INBORN-ERRORS, Immunoglobulin E, MESH: STAT3 Transcription Factor/immunology, Loss of heterozygosity, PRECISION MEDICINE, Transcription (biology), OF-FUNCTION MUTATIONS, STAT3, MESH: Transcription Factors/metabolism, CELL-DIFFERENTIATION, MESH: Th2 Cells/metabolism, MESH: Immunoglobulin E/immunology, MESH: Middle Aged, MESH: Gene Expression Regulation/immunology, Cell Differentiation, General Medicine, MESH: RNA, Messenger/metabolism, MESH: Immunoglobulin E/blood, MESH: Zinc Fingers/genetics, READ ALIGNMENT, MESH: Transcription, Genetic/immunology, MESH: Cell Nucleus/metabolism, MESH: Young Adult, [SDV.IMM]Life Sciences [q-bio]/Immunology, SIGNAL TRANSDUCER, Job Syndrome, MESH: Homozygote, STAT3 Transcription Factor, Cell type, MESH: Lymphocyte Count, MESH: Pedigree, MESH: STAT3 Transcription Factor/genetics, Immunology, Biology, Article, MESH: Job Syndrome/immunology, MESH: Genes, Recessive/genetics, DIFFERENTIAL EXPRESSION, MESH: Genes, Recessive/immunology, MESH: Job Syndrome/blood, MESH: Transcription Factors/genetics, 03 medical and health sciences, MESH: Whole Exome Sequencing, MESH: Exons/genetics, Humans, Transcription factor, Gene, MESH: Adolescent, MESH: Consanguinity, MESH: Humans, CLINICAL-FEATURES, MESH: Th17 Cells/metabolism, MESH: Th17 Cells/immunology, MESH: Cytokines/immunology, MESH: Adult, MESH: Loss of Function Mutation, MESH: Job Syndrome/genetics, MESH: Cell Differentiation/genetics, Molecular biology, MESH: Male, MESH: Th2 Cells/immunology, IL-21 RECEPTOR, 030104 developmental biology, Gene Expression Regulation, MESH: STAT3 Transcription Factor/metabolism, MESH: Promoter Regions, Genetic/genetics, MESH: Cell Differentiation/immunology, T-CELLS, STAT protein, biology.protein, Th17 Cells, MESH: Transcription Factors/immunology, MESH: Cytokines/metabolism, MESH: Female
Abstract: Comment in :Who regulates whom: ZNF341 is an additional player in the STAT3/TH17 song. [Sci Immunol. 2018]; International audience; Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.
Published: 2018

17. Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations

Author: Tardieu, C., Jung, S., Niederreither, K., Prasad, M., Hadj-Rabia, S., Philip, N., Mallet, A., Consolino, E., Sfeir, E., Noueiri, B., Chassaing, Nicolas, Dollfus, H., Manière, M.C., Bloch-Zupan, A., Clauss, F., Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Faculté de chirurgie dentaire - Strasbourg, Université de Strasbourg (UNISTRA), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Libanaise, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
Subjects: MESH: Adolescent, MESH: Ectoderm / pathology, MESH: Humans, MESH: Middle Aged, MESH: Adult, MESH: Phenotype, dental phenotype, bone, MESH: Tooth / pathology, MESH: Cone-Beam Computed Tomography, MESH: Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, MESH: Mutation / genetics, MESH: Wnt Proteins / genetics, oligodontia, WNT10A mutation, MESH: Mandible / pathology, MESH: Genetic Association Studies, MESH: Cohort Studies, extra-ectodermal signs, MESH: Heterozygote, MESH: Homozygote, MESH: Tooth / diagnostic imaging
Abstract: International audience; WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.
Published: 2017

18. Tissue kallikrein is required for the cardioprotective effect of Cyclosporin A in myocardial ischemia in the mouse

Author: C. Richer, M.-P. Vincent, G. Youcef, François Alhenc-Gelas, Anne Pizard, Elise Belaidi, M. Clemessy, L. Fazal, Ludovic Waeckel, G. Zadigue, Michel Ovize, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique [Nancy] (CIC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Subjects: Male, MESH: Signal Transduction, Myocardial Ischemia, Gene Expression, MESH: Myocytes, Cardiac, Mitochondrion, Pharmacology, MESH: Voltage-Dependent Anion Channel 1, Mitochondrial Membrane Transport Proteins, MESH: Mice, Knockout, MESH: Cyclosporine, Biochemistry, Mitochondria, Heart, Oxidative Phosphorylation, Cyclophilins, Mice, chemistry.chemical_compound, Cyclosporin a, Myocytes, Cardiac, MESH: Animals, Ischemic Postconditioning, Inner mitochondrial membrane, MESH: Heterozygote, Mice, Knockout, Cardioprotection, Tissue kallikrein, MPTP, Homozygote, MESH: Mitochondrial Membrane Transport Proteins, Mitochondria, Knockout mouse, Cyclosporine, cardiovascular system, Cardiac ischemia–reperfusion, MESH: Myocardial Ischemia, MESH: Mitochondria, Heart, Tissue Kallikreins, Cyclophilin D, Signal Transduction, MESH: Homozygote, Heterozygote, Cardiotonic Agents, MESH: Myocardium, MESH: Gene Expression, MESH: Rats, MESH: Tissue Kallikreins, Ischemia, Biology, MESH: Cyclophilins, MESH: Ischemic Postconditioning, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Oxidative Phosphorylation, medicine, Animals, cardiovascular diseases, MESH: Mice, Mitochondrial Permeability Transition Pore, Myocardium, Voltage-Dependent Anion Channel 1, MESH: Cardiotonic Agents, medicine.disease, MESH: Male, Rats, Cyclosporin A, Mitochondrial permeability transition pore, chemistry
Abstract: International audience; Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA. Homozygote and heterozygote TK deficient mice (TK(-/-), TK(+/-)) and wild type littermates (TK(+/+)) were subjected to cardiac ischemia-reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK(+/+) mice but had no effect in TK(+/-) and TK(-/-) mice. Cardiac mitochondria isolated from TK(-/-) mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK(+/+) mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD. Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.
Published: 2015

19. Homozygous mutations in VAMP 1 cause a presynaptic congenital myasthenic syndrome

Author: Salpietro, Vincenzo, Lin, Weichun, Vedove, Andrea Delle, Storbeck, Markus, Liu, Yun, Efthymiou, Stephanie, Manole, Andreea, Wiethoff, Sarah, Ye, Qiaohong, Saggar, Anand, McElreavey, Kenneth, Krishnakumar, Shyam S., Pitt, Matthew, Bello, Oscar D., Rothman, James E., Basel‐Vanagaite, Lina, Hubshman, Monika Weisz, Aharoni, Sharon, Manzur, Adnan Y., Wirth, Brunhilde, Houlden, Henry, University College of London [London] (UCL), University of Texas Southwestern Medical Center [Dallas], Center for Molecular Medicine [Cologne] (CMMC), University of Cologne, St George’s University Hospitals, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP), Yale School of Medicine [New Haven, Connecticut] (YSM), Great Ormond Street Hospital for Children [London] (GOSH), Tel Aviv University (TAU), Schneider Children’s Medical Center of Israel [Petah Tikva], Rabin Medical Center [Tel Aviv, Israël], This study was supported by the Wellcome Trust (WT093205MA, WT104033AIA), Medical Research Council (H.H.), European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement No. 2012-305121, B.W., H.H.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (H.H. and National Institutes of Health (NIH, NS-055028, W.L.)., SYNAPS Study Group, and European Project: 305121,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,NEUROMICS(2012)
Subjects: Male, MESH: Vesicle-Associated Membrane Protein 1, MESH: Myasthenic Syndromes, Congenital, MESH: Mice, Transgenic, MESH: Pedigree, Vesicle-Associated Membrane Protein 1, Neuromuscular Junction, Mice, Transgenic, Brief Communication, Consanguinity, Mice, Animals, Humans, MESH: Animals, MESH: Codon, Nonsense, Israel, MESH: Mice, Myasthenic Syndromes, Congenital, MESH: Consanguinity, MESH: Humans, Homozygote, MESH: Child, Preschool, MESH: Israel, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, MESH: Male, Pedigree, Disease Models, Animal, Kuwait, Codon, Nonsense, Child, Preschool, MESH: Kuwait, Female, MESH: Neuromuscular Junction, MESH: Disease Models, Animal, Brief Communications, MESH: Female, MESH: Homozygote
Abstract: International audience; We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.
Published: 2017

20. Aromatase Deficiency due to a Homozygous CYP19A1 Mutation in a 46,XX Egyptian Patient with Ambiguous Genitalia

Author: Inas, Mazen, Ken, McElreavey, Aya, Elaidy, Alaa K, Kamel, Mohamed S, Abdel-Hamid, National Research Centre - NRC (EGYPT), Génétique du Développement humain - Human developmental genetics, and Institut Pasteur [Paris] (IP)
Subjects: Adult, Male, MESH: Adrenal Hyperplasia, Congenital, endocrine system, MESH: Mutation, 46, XX Disorders of Sex Development, Adolescent, MESH: Metabolism, Inborn Errors, MESH: Pedigree, Disorders of Sex Development, MESH: Infertility, Male, MESH: Egypt, Young Adult, Aromatase, Ambiguous genitalia, MESH: Child, XX DSD, Humans, MESH: Aromatase, Child, Infertility, Male, MESH: Adolescent, MESH: 46, XX Disorders of Sex Development, MESH: Humans, Adrenal Hyperplasia, Congenital, CYP19A1 gene, Splice site mutation, Homozygote, Aromatase deficiency, MESH: Child, Preschool, MESH: Adult, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Exons, MESH: Male, Pedigree, MESH: Young Adult, Child, Preschool, Mutation, Gynecomastia, MESH: Gynecomastia, Female, Egypt, MESH: Disorders of Sex Development, MESH: Exons, MESH: Female, Metabolism, Inborn Errors, MESH: Homozygote
Abstract: International audience; Aromatase deficiency (AD) is a very rare disorder resulting from mutations in the CYP19A1 gene encoding aromatase, a cytochrome P450 enzyme that plays a pivotal role in androgen conversion to estrogens. AD is inherited in an autosomal recessive trait, and to date only 35 cases have been described in the literature. Herein, we depict a new patient reared as a male, who presented at the age of 21 years with no palpable testis, hypoplastic scrotum, penis-like phallus (3 cm), and penoscrotal hypospadias. The patient was born to consanguineous parents, his karyotype was 46,XX, and SRY was negative. Pelvic sonar showed a small hypoplastic uterus, and no testis could be identified. Serum testosterone was within the reference range of females along with high gonadotropins. Pathology of gonadal biopsy showed ovarian stroma negative for oocytic follicle consistent with streak gonads. All these data were suggestive of AD, which was subsequently confirmed by molecular investigation of the CYP19A1 gene. A homozygous splice site mutation in the donor splice site of exon 9 was identified, c.1263 + 1G>T. This is the first report of such a rare disorder in an Egyptian patient. Our results reinforce the importance of considering AD in patients with 46,XX disorders of sex development after ruling out congenital adrenal hyperplasia.
Published: 2017

21. Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis

Author: Sonia Abdelhak, Mariem Ben Rekaya, Manel Jerbi, M. Zghal, Mariem Chargui, Meriem Jones, Houda Yacoub-Youssef, Ken McElreavey, Anu Bashamboo, Tommaso Pippucci, Hamza Dallali, Majdi Nagara, Mohamed Alibi, Giovanni Romeo, Abdelhamid Barakat, Olfa Messaoud, Haifa Jmel, Chokri Naouali, Yosra Bouyacoub, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Tunis El Manar (UTM), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Moléculaire Humaine, Institut Pasteur du Maroc, Hôpital Charles Nicolle [Tunis], This work was supported by the Tunisian Ministry of Public Health, the Ministry of Higher Education and Scientific Research (LR11IPT05), the E.C. Grant agreement N° 295097 for FP7 project GM-NCD-Inco (www.genomedika.org), The Actions Concertees Interpasteuriennes (ACIP) project 'Post genomic tools for disease gene identification: pilot project of Maghrebian populations', and the Projet collaborative interne (PCI) (IPT/LR05/Projet). MBR is recipient of a Mobidoc Post-Doc Fellowship under the Programme d’Appui au Système de recherche et d’Innovation (PASRI-Europe Aid)., European Project: 295097,EC:FP7:INCO,FP7-INCO-2011-6,GM_NCD_IN_CO(2011), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, XP-E, XP-D, Biochemistry, MESH: Xeroderma Pigmentosum Group D Protein/genetics, MESH: DNA-Binding Proteins/genetics, MESH: Xeroderma Pigmentosum/genetics, Exome sequencing, Genetics, Sanger sequencing, ROH, MESH: Xeroderma Pigmentosum/diagnosis, Homozygote, 3. Good health, Pedigree, Complementation, DNA-Binding Proteins, Phenotype, MESH: Young Adult, Mutation (genetic algorithm), symbols, WES, Identification (biology), MESH: Tunisia, MESH: Homozygote, Adult, Xeroderma pigmentosum, MESH: Mutation, Tunisia, Adolescent, MESH: Pedigree, Genetic counseling, Founder mutations, Dermatology, Biology, MESH: Phenotype, 03 medical and health sciences, symbols.namesake, Young Adult, MESH: Whole Exome Sequencing, Exome Sequencing, medicine, Humans, Molecular Biology, Xeroderma Pigmentosum Group D Protein, MESH: Adolescent, Xeroderma Pigmentosum, MESH: Humans, MESH: Adult, medicine.disease, 030104 developmental biology, Mutation, ERCC2, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome. Objectives First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals. Methods Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors. Results Screening for functional variations showed the presence of the ERCC2 p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delG DDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness. Conclusion To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.
Published: 2016

22. Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

Author: Anne Puel, Stephanie Boisson-Dupuis, Davood Mansouri, Avinash Abhyankar, Shen-Ying Zhang, Silvia SÁNCHEZ-RAMÓN, Jean-Laurent Casanova, Jacinta Bustamante, Antonio Condino-Neto, Francois Vandenesch, Bertrand Boisson, Vincent Pedergnana, Sara sebnem Kilic, Emmanuelle Jouanguy, Aurélie Cobat, Didier Raoult, Melike Emiroglu, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], New York Genome Center [New York], New York Genome Center, Hôpital militaire d'instruction Mohammed V [Rabat, Maroc], CHU Ibn Rochd [Casablanca], Université Hassan II [Casablanca] (UH2MC), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), and Exome/Array Consortium: Waleed Al-Herz, Cigdem Arikan, Peter Arkwright, Cigdem Aydogmus, Olivier Bernard, Lizbeth Blancas-Galicia, Stéphanie Boisson-Dupuis, Damien Bonnet, Omar Boudghene Stambouli, Lobna Boussofara, Jeannette Boutros, Jacinta Bustamante, Michael Ciancanelli, Theresa Cole, Antonio Condino-Neto, Mukesh Desai, Claire Fieschi, José Luis Franco, Philippe Ichai, Emmanuelle Jouanguy, Melike Keser-Emiroglu, Sara S Kilic, Seyed Alireza Mahdaviani, Nizar Mahlhoui, Davood Mansouri, Nima Parvaneh, Capucine Picard, Anne Puel, Didier Raoult, Nima Rezaei, Ozden Sanal, Silvia Sanchez Ramon, François Vandenesch, Guillaume Vogt, Shen-Ying Zhang
Subjects: 0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Population, MESH: Genetic Linkage, Genome-wide association study, Runs of Homozygosity, Biology, genotyping array, 03 medical and health sciences, Consanguinity, Middle East, 0302 clinical medicine, Humans, linkage analysis, education, Exome sequencing, MESH: Consanguinity, Linkage (software), Genetics, education.field_of_study, MESH: Humans, Multidisciplinary, Homozygote, population structure, Biological Sciences, Disease gene identification, MESH: Male, MESH: North America, Minor allele frequency, 030104 developmental biology, homozygosity mapping, MESH: Middle East, MESH: Genome-Wide Association Study, North America, Female, exome sequencing, MESH: Female, Inbreeding, 030217 neurology & neurosurgery, MESH: Homozygote, Genome-Wide Association Study
Abstract: International audience; Significance We compared the information provided by whole-exome sequencing (WES) and genome-wide single-nucleotide variant arrays in terms of principal component analysis, homozygosity rate estimation, and linkage analysis using 110 subjects originating from different regions of the world. WES provided an accurate prediction of population substructure using high-quality variants with a minor allele frequency > 2% and reliable estimation of homozygosity rates using runs of homozygosity. Finally, homozygosity mapping in 15 consanguineous families showed that WES led to powerful linkage analyses, particularly in coding regions. Overall, our study shows that WES could be used for several analyses that are very helpful to optimize the search for disease-causing exome variants. AbstractPrincipal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions.
Published: 2016

23. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP

Author: Raoudha Zouari, Nicolas Thierry-Mieg, Thomas Karaouzène, Zine Eddine Kherraf, Hoi Chang Lee, Lazhar Halouani, Serge Nef, Charles Coutton, Christophe Arnoult, Rafael A. Fissore, Chema Triki, Jessica Escoffier, Sergey N. Savinov, Guillaume Martinez, Sandra Yassine, Pierre F. Ray, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), Clinique de Promotion des Sciences de la Reproduction, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de la reproduction les Jasmins, Centre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), entre of Reproductive Medicine and Prenatal Diagnosis (CMRDP), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Thierry-Mieg, Nicolas
Subjects: Male, Models, Molecular, 0301 basic medicine, MESH: Sperm-Ovum Interactions, medicine.medical_treatment, In Vitro Oocyte Maturation Techniques, MESH: Amino Acid Sequence, MESH: Base Sequence, Intracytoplasmic sperm injection, Mice, Phosphoinositide Phospholipase C, 0302 clinical medicine, Missense mutation, ddc:576.5, MESH: Animals, MESH: Embryo Loss, Genetics (clinical), Sperm motility, C2 domain, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030219 obstetrics & reproductive medicine, Homozygote, MESH: Spermatozoa, Articles, General Medicine, MESH: Sperm Motility, Spermatozoa, MESH: Gene Expression Regulation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Transport protein, Cell biology, Protein Transport, Embryo Loss, Sperm Motility, Female, MESH: Seminal Plasma Proteins, MESH: Models, Molecular, MESH: Homozygote, Adult, medicine.medical_specialty, MESH: Protein Transport, MESH: Mutation, Molecular Sequence Data, MESH: Sequence Alignment, MESH: Carrier Proteins, Biology, MESH: Infertility, Male, MESH: Calcium Signaling, MESH: Oocytes, 03 medical and health sciences, Internal medicine, Genetics, medicine, MESH: Phosphoinositide Phospholipase C, Animals, Humans, Amino Acid Sequence, Calcium Signaling, Molecular Biology, MESH: Mice, Infertility, Male, Sperm-Ovum Interactions, MESH: Humans, MESH: In Vitro Oocyte Maturation Techniques, MESH: Molecular Sequence Data, Base Sequence, Siblings, Seminal Plasma Proteins, Oocyte activation, MESH: Adult, Sperm, MESH: Male, MESH: Siblings, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Mutation, Oocytes, Carrier Proteins, Sequence Alignment, MESH: Female
Abstract: International audience; In mammals, sperm-oocyte fusion initiates Ca(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the likely candidate to induce oocyte activation. Recently, PAWP, a sperm-born tryptophan domain-binding protein coded by WBP2NL, was proposed to serve the same purpose. Here, we studied two infertile brothers exhibiting normal sperm morphology but complete fertilization failure after intracytoplasmic sperm injection. Whole exomic sequencing evidenced a missense homozygous mutation in PLCZ1, c.1465A>T; p.Ile489Phe, converting Ile 489 into Phe. We showed the mutation is deleterious, leading to the absence of the protein in sperm, mislocalization of the protein when injected in mouse GV and MII oocytes, highly abnormal Ca(2+) transients and early embryonic arrest. Altogether these alterations are consistent with our patients' sperm inability to induce oocyte activation and initiate embryo development. In contrast, no deleterious variants were identified in WBP2NL and PAWP presented normal expression and localization. Overall we demonstrate in humans, the absence of PLCZ1 alone is sufficient to prevent oocyte activation irrespective of the presence of PAWP. Additionally, it is the first mutation located in the C2 domain of PLCZ1, a domain involved in targeting proteins to cell membranes. This opens the door to structure-function studies to identify the conserved amino acids of the C2 domain that regulate the targeting of PLCZ1 and its selectivity for its lipid substrate(s).
Published: 2016

24. A homozygous PAX3 mutation leading to severe presentation of Waardenburg syndrome with a prenatal diagnosis

Author: Mousty, Eve, Issa, Sarah, Grosjean, Frédéric, Col, Jean-Yves, Khau van Kien, Philippe, Perez, Marie-Josée, Petrov, Yuliya, Reboul, Dorothée, Faubert, Emmanuelle, Le Gac, Marie-Pascale, Bondurand, Nadège, Chiesa, Jean, Pingault, Véronique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Henri Duffaut (Avignon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Herrada, Anthony
Subjects: MESH: Waardenburg Syndrome, MESH: Humans, MESH: Pregnancy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Young Adult, MESH: Nuchal Translucency Measurement, MESH: PAX3 Transcription Factor, MESH: Paired Box Transcription Factors, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Homozygote
Abstract: International audience; What's already known about this topic? Waardenburg syndrome is a form of deafness associated with pigmentation abnormalities, two features that cannot been diagnosed in a fetus. Musculoskeletal abnormalities of the upper limbs are associated in Waardenburg syndrome type III (WS3).What does this study add? We document two cases of WS3 diagnosed at first trimester of pregnancy, because of a homozygous mutation in PAX3. Ultrasound examinations revealed increased nuchal translucency, lack of active movements, bilateral club hands and club feet, and neural abnormalities.
Published: 2015

25. Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations

Author: Franck Sturtz, Jean-Michel Vallat, Robert A. Ouvrier, Corinne Magdelaine, Danqing Zhu, S. Grew, Monique M. Ryan, Garth A. Nicholson, Service de Biochimie et Génétique Moléculaire [CHU Limoges], CHU Limoges, Biomolécules Thérapies anti-tumorales (EA4021), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), and Service de Neurologie [CHU Limoges]
Subjects: Male, Pathology, Wallerian degeneration, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, DNA Mutational Analysis, Inheritance Patterns, MESH: Genetic Markers, Compound heterozygosity, medicine.disease_cause, GTP Phosphohydrolases, MESH: Genotype, 0302 clinical medicine, Genotype, MESH: DNA Mutational Analysis, Age of Onset, MESH: Heterozygote, Genes, Dominant, Genetics, 0303 health sciences, Mutation, MESH: Genetic Testing, Homozygote, MESH: Genetic Predisposition to Disease, MESH: Mitochondrial Proteins, Peripheral Nervous System Diseases, Phenotype, 3. Good health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Membrane Proteins, MESH: Peripheral Nervous System Diseases, MESH: Homozygote, Adult, Genetic Markers, MESH: Axons, Heterozygote, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, Hearing Loss, Sensorineural, Biology, Mitochondrial Proteins, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Predisposition to Disease, Genetic Testing, Peripheral Nerves, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Membrane Proteins, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Heterozygote advantage, MESH: Peripheral Nerves, medicine.disease, MESH: Male, Axons, Peripheral neuropathy, MESH: Hearing Loss, Sensorineural, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, nervous system, Neurology (clinical), MESH: Inheritance Patterns, Age of onset, MESH: Wallerian Degeneration, MESH: Genes, Dominant, Wallerian Degeneration, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Objective: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations.Methods: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined.Results: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations.Conclusion: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.
Published: 2008

26. SPG11: a consistent clinical phenotype in a family with homozygous Spatacsin truncating mutation

Author: Alessio Di Fonzo, Federica Locatelli, Stefania Corti, Giovanni Stevanin, Antonella Costa, Giacomo P. Comi, Nereo Bresolin, Roberto Del Bo, S. Ghezzi, Department of Neurological Sciences, University of Milan, IRCCS Eugenio Medea, IRCCS, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroradiologic Unit, IRCCS Foundation, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Università degli Studi di Milano = University of Milan (UNIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Linkage disequilibrium, MESH: Base Sequence, medicine.disease_cause, Genetic analysis, Linkage Disequilibrium, MESH: Magnetic Resonance Imaging, Corpus Callosum, 0302 clinical medicine, Twins, Dizygotic, MESH: Proteins, Frameshift Mutation, Genetics (clinical), Sequence Deletion, Genetics, MESH: Spastic Paraplegia, Hereditary, 0303 health sciences, Mutation, Homozygote, MESH: DNA, MESH: Frameshift Mutation, MESH: Sequence Deletion, MESH: Amino Acid Substitution, Magnetic Resonance Imaging, Pedigree, Phenotype, MESH: Linkage Disequilibrium, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Homozygote, Adult, MESH: Pedigree, Hereditary spastic paraplegia, Biology, MESH: Phenotype, MESH: Corpus Callosum, Frameshift mutation, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, Gene, Loss function, 030304 developmental biology, MESH: Humans, Base Sequence, MESH: Twins, Dizygotic, Spastic Paraplegia, Hereditary, Proteins, MESH: Adult, DNA, medicine.disease, MESH: Male, Human genetics, Amino Acid Substitution, MESH: Female, 030217 neurology & neurosurgery
Abstract: Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Here, we describe clinical and genetic features in an Italian family affected by autosomal recessive HSP (ARHSP) with mental impairment and thin corpus callosum (TCC). In both affected subjects, genetic analysis revealed the presence of a homozygous small deletion (733_734delAT) leading to a frameshift (M245VfsX) within the coding region of SPG11 gene, encoding spatacsin. This finding is the first independent confirmation that spatacsin loss of function mutations cause ARHPS-TCC.
Published: 2007

27. Matthew-Wood Syndrome Is Caused by Truncating Mutations in the Retinol-Binding Protein Receptor Gene STRA6

Author: Michel Vekemans, Christelle Golzio, Bettina Grattagliano-Bessières, Jelena Martinovic-Bouriel, Arnold Munnich, Sophie Delahaye, Tania Attié-Bitach, Stanislas Lyonnet, Heather C. Etchevers, Soumaya Mougou-Zrelli, Maryse Bonnière, Férechté Encha-Razavi, Sophie Thomas, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Institut de Puériculture de Paris (IPP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Puériculture de Paris ( IPP ), and Assistance publique - Hôpitaux de Paris (AP-HP)
Subjects: Lung Diseases, MESH: Sequence Analysis, DNA, Vitamin A transport, MESH : Polymorphism, Genetic, MESH : Receptors, Cell Surface, MESH : Gene Deletion, MESH: Genetic Markers, MESH : Syndrome, MESH : Frameshift Mutation, MESH : Microphthalmos, Consanguinity, MESH: Lung Diseases, Exon, MESH : Exons, 0302 clinical medicine, Microphthalmos, MESH : Genetic Markers, MESH: Syndrome, Genetics(clinical), Frameshift Mutation, Genetics (clinical), MESH: Receptors, Cell Surface, 0303 health sciences, Fetal Growth Retardation, MESH : Lung Diseases, Homozygote, MESH: Frameshift Mutation, Exons, Syndrome, Pedigree, MESH: Membrane Proteins, MESH : Mutation, MESH: Homozygote, Genetic Markers, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Pedigree, MESH: Microphthalmos, MESH: Fetal Growth Retardation, Receptors, Cell Surface, Biology, Frameshift mutation, 03 medical and health sciences, Pulmonary hypoplasia, MESH : Homozygote, Report, MESH : Consanguinity, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Abnormalities, Multiple, MESH : Fetal Growth Retardation, MESH : Haplotypes, 030304 developmental biology, MESH: Consanguinity, MESH : Mutagenesis, Insertional, Polymorphism, Genetic, MESH: Humans, Anophthalmia, MESH : Abnormalities, Multiple, Genetic heterogeneity, MESH : Humans, Pulmonary Agenesis, Membrane Proteins, Sequence Analysis, DNA, MESH: Haplotypes, medicine.disease, Molecular biology, Mutagenesis, Insertional, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Haplotypes, MESH: Mutagenesis, Insertional, MESH : Membrane Proteins, MESH: Gene Deletion, MESH : Pedigree, [ SDV.BDD.EO ] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, MESH: Exons, Matthew Wood syndrome, Gene Deletion, 030217 neurology & neurosurgery, MESH : Sequence Analysis, DNA
Abstract: International audience; Retinoic acid (RA) is a potent teratogen in all vertebrates when tight homeostatic controls on its endogenous dose, location, or timing are perturbed during early embryogenesis. STRA6 encodes an integral cell-membrane protein that favors RA uptake from soluble retinol-binding protein; its transcription is directly regulated by RA levels. Molecular analysis of STRA6 was undertaken in two human fetuses from consanguineous families we previously described with Matthew-Wood syndrome in a context of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation. The fetuses had either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7 predicting a premature stop codon in STRA6 transcripts. Five other fetuses presenting at least one of the two major signs of clinical anophthalmia or pulmonary hypoplasia with at least one of the two associated signs of diaphragmatic closure defect or cardiopathy had no STRA6 mutations. These findings suggest a molecular basis for the prenatal manifestations of Matthew-Wood syndrome and suggest that phenotypic overlap with other associations may be due to genetic heterogeneity of elements common to the RA- and fibroblast growth factor-signaling cascades.
Published: 2007

28. Gain of affinity point mutation in the serotonin receptor gene 5-HT2Droaccelerates germband extension movements duringDrosophilagastrulation

Author: Jean-Marie Launay, J L Vonesch, Bérénice Schaerlinger, Luc Maroteaux, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Maroteaux, Luc
Subjects: Models, Molecular, Embryo, Nonmammalian, MESH: Drosophila, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Ectoderm, MESH: Base Sequence, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, chemistry.chemical_compound, 0302 clinical medicine, Cell Movement, MESH: Animals, Neurotransmitter, Receptor, MESH: Cell Movement, Genetics, 0303 health sciences, Homozygote, Embryo, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drosophila, MESH: Models, Molecular, MESH: Body Patterning, MESH: Homozygote, Serotonin, animal structures, MESH: Receptors, Serotonin, 5-HT2, Molecular Sequence Data, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, MESH: Sequence Homology, Nucleic Acid, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Sequence Homology, Nucleic Acid, MESH: Gastrula, medicine, Animals, Point Mutation, 5-HT receptor, Body Patterning, MESH: Point Mutation, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Point mutation, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Embryo, Nonmammalian, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gastrula, Gastrulation, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, chemistry, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Serotonin, Receptors, Serotonin, 5-HT2, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Serotonin (5-HT) not only works as a neurotransmitter in the nervous system, but also as a morphogenetic factor during early embryogenesis. In Drosophila, a previous report showed that embryos that lack the 5-HT(2Dro) receptor locus, display abnormal gastrulation movements. In this work, we screened for point mutations in the 5-HT(2Dro) receptor gene. We identified one point mutation that generates a gain of serotonin affinity for the receptor and affects germband extension: 5-HT(2Dro) (C1644). Embryos homozygous for this point mutation display a fourfold increase in the maximal speed of ectodermal cell movements during the rapid phase of germband extension. Homozygous 5-HT(2Dro) (C1644) embryos present a cuticular phenotype, including a total lack of denticle belt. Identification of this gain of function mutation shows the participation of serotonin in the regulation of the cell speed movements during the germband extension and suggests a role of serotonin in the regulation of cuticular formation during early embryogenesis.
Published: 2007

29. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition

Author: Jeremie Vitte, Anne Tarrade, Sabrina Courageot, Judith Melki, Etienne Mouisel, Delphine Charvin, Alain Thorel, Andrée Dierich, Nuria Fonknechten, Danielle Seilhean, Coralie Fassier, Natacha Roblot, Leticia Peris, Jean Jacques Hauw, Neurogenetique Moleculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Centre des Matériaux (MAT), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collaboration, Centre des Matériaux (CDM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Andrieux, Annie
Subjects: Central Nervous System, Spastin, MESH: Base Sequence, Microtubules, MESH: Mice, Knockout, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Axon, Cells, Cultured, Genetics (clinical), MESH: Heterozygote, Adenosine Triphosphatases, Cerebral Cortex, Mice, Knockout, Motor Neurons, Genetics, 0303 health sciences, Behavior, Animal, MESH: Microtubules, Homozygote, Exons, General Medicine, Cell biology, medicine.anatomical_structure, MESH: Microscopy, Electron, Transmission, Microtubule-Associated Proteins, MESH: Motor Neurons, MESH: Homozygote, MESH: Cells, Cultured, Heterozygote, MESH: Axons, MESH: Mutation, Neurite, Microtubule-associated protein, MESH: Biological Transport, Blotting, Western, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Microscopy, Electron, Transmission, Microtubule, Neurites, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Adenosine Triphosphatases, medicine, Animals, MESH: Blotting, Western, MESH: Central Nervous System, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Growth cone, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Molecular Biology, 030304 developmental biology, Base Sequence, Biological Transport, MESH: Neurites, Axons, MESH: Cerebral Cortex, Protein Structure, Tertiary, MESH: Microtubule-Associated Proteins, MESH: Gene Deletion, Mutation, Axoplasmic transport, Neuron, MESH: Exons, Gene Deletion, 030217 neurology & neurosurgery
Abstract: International audience; Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated alpha-tubulin and dynamic microtubules composed almost exclusively of tyrosinated alpha-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.
Published: 2006

30. Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells

Author: Gilbert de Murcia, Helfrid Hochegger, Valérie Schreiber, Donniphat Dejsuphong, Guang Yu Zhao, Shunichi Takeda, Alihossein Saberi, Eiichiro Sonoda, Toru Fukushima, Noritaka Adachi, Hideki Koyama, Mitsuko Masutani, Ciaran G. Morrison, National University of Ireland [Galway] (NUI Galway), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: sister-chromatid exchanges, Ku80, mammalian-cells, homologous recombination, medicine.disease_cause, functional interaction, DNA Ligase ATP, 0302 clinical medicine, MESH: Animals, MESH: Ku Autoantigen, Recombination, Genetic, chemistry.chemical_classification, B-Lymphocytes, 0303 health sciences, Mutation, Ku70, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Neuroscience, Homozygote, gene-disruption, MESH: Chickens, MESH: DNA, poly(adp-ribose) polymerase-2 parp-2, Antigens, Nuclear, Base excision repair, DNA-Binding Proteins, Non-homologous end joining, Phenotype, 030220 oncology & carcinogenesis, MESH: Camptothecin, v(d)j recombination, MESH: Recombination, Genetic, Poly(ADP-ribose) Polymerases, ionizing radiation, MESH: Homozygote, MESH: DNA Ligases, mice, MESH: Mutation, DNA Ligases, DNA damage, mediated DNA-damage, Biology, Transfection, MESH: Phenotype, base excision repair, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, mms, 03 medical and health sciences, MESH: DNA Ligase ATP, strand break repair, MESH: B-Lymphocytes, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Ku Autoantigen, MESH: Antigens, Nuclear, Molecular Biology, 030304 developmental biology, MESH: DNA Damage, DNA ligase, General Immunology and Microbiology, MESH: Transfection, camptothecin, MESH: Poly(ADP-ribose) Polymerases, fungi, DNA, Molecular biology, MESH: Cell Line, enzymes and coenzymes (carbohydrates), chemistry, topoisomerase-i, Homologous recombination, Chickens, MESH: DNA-Binding Proteins, DNA Damage
Abstract: Parp-1 and Parp-2 are activated by DNA breaks and have been implicated in the repair of DNA single-strand breaks (SSB). Their involvement in double-strand break (DSB) repair mediated by homologous recombination (HR) or nonhomologous end joining (NHEJ) remains unclear. We addressed this question using chicken DT40 cells, which have the advantage of carrying only a PARP-1 gene but not a PARP-2 gene. We found that PARP-1(-/-) DT40 mutants show reduced levels of HR and are sensitive to various DSB-inducing genotoxic agents. Surprisingly, this phenotype was strictly dependent on the presence of Ku, a DSB-binding factor that mediates NHEJ. PARP-1/KU70 double mutants were proficient in the execution of HR and displayed elevated resistance to DSB-inducing drugs. Moreover, we found deletion of Ligase IV, another NHEJ gene, suppressed the camptothecin of PARP-1(-/-) cells. Our results suggest a new critical function for Parp in minimizing the suppressive effects of Ku and the NHEJ pathway on HR.
Published: 2006

31. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles

Author: Deborah Hoogstraten, Wibeke J. Van Leeuwen, J. G. M. Huijmans, Frédéric Coin, Jean-Marc Egly, Marieke van de Ven, Judith Jans, Wendy Toussaint, James R. Mitchell, Jaan-Olle Andressoo, H. Bing Thio, Gijsbertus T. J. van der Horst, Jan H.J. Hoeijmakers, Jan de Wit, Jan de Boer, Molecular Genetics, Clinical Genetics, Dermatology, Radiology & Nuclear Medicine, Toussaint, Jean-Luc, Department of Cell Biology and Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Department of dermatology, Department of Experimental Radiology, This research was supported by the Netherlands Organization for Scientific Research (NWO) through the foundation of the Research Institute for Diseases of the Elderly, as well as grants from the National Institutes of Health (1PO1 AG17242-02), National Institute of Environmental Health Sciences (1UO1 ES011044), European Commission (QRTL-1999-02002), and the Dutch Cancer Society (EUR 99-2004). JRM was a fellow of the Damon Runyon Cancer Research Fund (DRG 1677)., and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: Transcription, Genetic, Eukaryotes, Trichothiodystrophy, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular Biology/Structural Biology, Compound heterozygosity, Test cross, Cockayne syndrome, Loss of heterozygosity, Mice, Progeria, 0302 clinical medicine, Lethal allele, MESH: Animals, Biology (General), Growth Disorders, Mammals, Genetics, 0303 health sciences, MESH: Transcription Factor TFIIH, General Neuroscience, Homozygote, Ichthyosis, MESH: Xeroderma Pigmentosum Group D Protein, MESH: Growth Disorders, Mus (Mouse), Null allele, Phenotype, Hemizygote, Synopsis, General Agricultural and Biological Sciences, MESH: Ichthyosis, MESH: Homozygote, Research Article, Xeroderma pigmentosum, Ultraviolet Rays, QH301-705.5, Evolution, MESH: Progeria, Genes, Recessive, Biology, MESH: Phenotype, Genetics/Genomics/Gene Therapy, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, Allele, MESH: Mice, Alleles, MESH: Genes, Recessive, Xeroderma Pigmentosum Group D Protein, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, Genetic carrier, General Immunology and Microbiology, MESH: Alleles, MESH: Transcription, Genetic, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Mice, Inbred C57BL, MESH: Hair Diseases, Genes, Lethal, MESH: Ultraviolet Rays, MESH: Genes, Lethal, Hair Diseases, Transcription Factor TFIIH, 030217 neurology & neurosurgery, DNA Damage
Abstract: Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals., Effects of mutations in Xpd were investigated in mice. Compound heterozygotes of otherwise homozygous lethal alleles demonstrated interallelic complementation and partial phenotypic rescue of XPD-related disease symptoms.
Published: 2006

32. Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation

Author: Jean-Paul Leroy, Jordi Molgó, Julien Barbier, Michel Fardeau, Daniel Hantaï, F. Andreux, Pascale Richard, Jeanine Koenig, Cassandra Prioleau, Bruno Eymard, Eriko Yasaki, Philippe Dartevelle, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Paediatrics, Tokyo Women's Medical University (TWMU), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Morvan, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Chirurgie thoracique, Centre chirurgical Marie Lannelongue, Université Bordeaux Segalen - Bordeaux 2, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Chirurgical Marie Lannelongue (CCML)
Subjects: Male, Biopsy, DNA Mutational Analysis, Neuromuscular transmission, Muscle Proteins, Chromosome Disorders, Receptors, Nicotinic, medicine.disease_cause, Synaptic Transmission, MESH: Down-Regulation, Membrane Potentials, MESH: Biopsy, 0302 clinical medicine, Gene Frequency, Medicine, MESH: DNA Mutational Analysis, Genetics (clinical), MESH: Muscle, Skeletal, MESH: Chromosome Disorders, 0303 health sciences, Mutation, MESH: Electrophysiology, medicine.diagnostic_test, Homozygote, Congenital myasthenic syndrome, Pedigree, Electrophysiology, medicine.anatomical_structure, Neurology, MESH: Receptors, Nicotinic, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, MESH: Homozygote, Adult, MESH: Myasthenic Syndromes, Congenital, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, Neuromuscular Junction, Synaptic Membranes, Down-Regulation, Genes, Recessive, In Vitro Techniques, Neuromuscular junction, MESH: Muscle Proteins, MESH: Receptor Aggregation, 03 medical and health sciences, Internal medicine, MESH: Synaptic Transmission, MESH: Gene Frequency, Humans, MESH: Membrane Potentials, Muscle, Skeletal, MESH: Genes, Recessive, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, MESH: Humans, Muscle biopsy, business.industry, Receptor Aggregation, Fatigable weakness, Muscle weakness, MESH: Adult, MESH: Haplotypes, medicine.disease, MESH: Synaptic Membranes, MESH: Male, Endocrinology, Haplotypes, Pediatrics, Perinatology and Child Health, MESH: Neuromuscular Junction, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract: Congenital myasthenic syndromes are rare heterogeneous hereditary disorders, which lead to defective neuromuscular transmission resulting in fatigable muscle weakness. Post-synaptic congenital myasthenic syndromes are caused by acetylcholine receptor kinetic abnormalities or by acetylcholine receptor deficiency. Most of the congenital myasthenic syndromes with acetylcholine receptor deficiency are due to mutations in acetylcholine receptor subunit genes. Some have recently been attributed to mutations in the rapsyn gene. Here, we report the case of a 28-year-old French congenital myasthenic syndrome patient who had mild diplopia and fatigability from the age of 5 years. His muscle biopsy revealed a marked reduction in rapsyn and acetylcholine receptor at neuromuscular junctions together with a simplification of the subneural apparatus structure. In this patient, we excluded mutations in the acetylcholine receptor subunit genes and identified the homozygous N88K rapsyn mutation, which has already been shown by cell expression to impair rapsyn and acetylcholine receptor aggregation at the neuromuscular junction. The detection of the N88K mutation at the heterozygous state in five of 300 unrelated control subjects shows that this mutation is not infrequent in the healthy population. Electrophysiological measurements on biopsied intercostal muscle from this patient showed that his rapsyn mutation-induced fatigable weakness is expressed not only in a diminution in acetylcholine receptor membrane density but also in a decline of endplate potentials evoked at low frequency.
Published: 2004

33. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella

Author: Pierre-Simon Jouk, Nicolas Thierry-Mieg, Pierre F. Ray, Karine Pernet-Gallay, Thomas Karaouzène, Denise Escalier, Charles Coutton, Christophe Arnoult, Virginie Pierre, Marie Bidart, Sylviane Hennebicq, Mariem Ben Khelifa, Raoudha Zouari, Didier Grunwald, John Rendu, Aminata Touré, Julie Delaroche, Sandra Yassine, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory ( LR11IPT05 ), Université Tunis El Manar ( UTM ) -Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), Université Joseph Fourier - Grenoble 1 ( UJF ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Genetique Chromosomique, CHU Grenoble, Clinique de Promotion des Sciences de la Reproduction - Les Jasmins ( CPSR ), Clinique de Promotion des Sciences de la Reproduction, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Institut de Biologie et de Pathologie ( DBTP ), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation ( CECOS ), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), This work was supported by the research grant ICG2I funded by the program GENOPAT 2009 from the French Research Agency (ANR)., ANR-09-GENO-0013,ICG2I,Identification et Caractérisation de gènes impliqués dans l'infertilité. ( 2009 ), Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université Joseph Fourier - Grenoble 1 (UJF), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Chromosomique [CHU de Grenoble], Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie et de Pathologie (DBTP), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamiques Cellulaire, Tissulaire & Microscopie fonctionnelle (TIMC-IMAG-DyCTiM), ANR-09-GENO-0013,ICG2I,Identification et Caractérisation de gènes impliqués dans l'infertilité.(2009), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université Tunis El Manar (UTM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Male, MESH: Sequence Analysis, DNA, Axoneme, MESH : RNA, Messenger, [SDV]Life Sciences [q-bio], MESH: RNA Splice Sites, Male infertility, 0302 clinical medicine, MESH : Axoneme, Testis, MESH : Infertility, Male, Genetics(clinical), MESH: Genetic Variation, Genetics (clinical), Sperm motility, Primary ciliary dyskinesia, Genetics, 0303 health sciences, 030219 obstetrics & reproductive medicine, MESH: Testis, Cilium, Homozygote, MESH : Kartagener Syndrome, MESH: Sperm Motility, MESH: Axoneme, MESH : Axonemal Dyneins, Flagella, Sperm Motility, MESH: Axonemal Dyneins, MESH : Mutation, MESH : RNA Splice Sites, MESH: Homozygote, Infertility, MESH: Mutation, MESH : Male, Dynein, Flagellum, Biology, MESH: Infertility, Male, MESH: Flagella, 03 medical and health sciences, MESH : Cilia, MESH : Homozygote, MESH: Cilia, MESH : Genetic Variation, Report, medicine, Humans, Cilia, RNA, Messenger, Infertility, Male, 030304 developmental biology, MESH: RNA, Messenger, MESH : Testis, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Sperm flagellum, Kartagener Syndrome, MESH : Humans, MESH : Sperm Tail, Genetic Variation, Axonemal Dyneins, Sequence Analysis, DNA, medicine.disease, MESH: Male, MESH: Sperm Tail, MESH : Sperm Motility, Sperm Tail, Mutation, MESH: Kartagener Syndrome, RNA Splice Sites, MESH : Flagella, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH : Sequence Analysis, DNA
Abstract: International audience; Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.
Published: 2014

34. A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

Author: Tania Attié-Bitach, Sophie Saunier, Mandy Kwong, Nadia Elkhartoufi, Enza Maria Valente, Isabelle Perrault, Joseph G. Gleeson, Alessia Micalizzi, Stéphanie Le Corre, Marta Romani, Julie Litzler, Lydie Burglen, Iain A. Drummond, Kevin J. Wright, Avinash Abhyankar, Julien Saada, Jean-Laurent Casanova, Stanislas Lyonnet, Nathalie Boddaert, Nicolas Chassaing, Arnold Munnich, Jeanne Amiel, Peter K. Jackson, Emilie Filhol, Michel Vekemans, Ferechté Encha-Ravazi, Wolfgang Baehr, Sophie Thomas, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Genentech, Inc., Genentech, Inc. [San Francisco], Massachusetts General Hospital [Boston], Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universita degli Studi di Messina, Rockefeller University [New York], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], Génétique Humaine des Maladies Infectieuses (Inserm U980), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Utah, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Howard Hughes Medical Institute (HHMI), University of California [San Diego] (UC San Diego), University of California, and Harvard Medical School [Boston] (HMS)
Subjects: Male, Models, Molecular, Proteomics, MESH: Sequence Analysis, DNA, MESH: Cilia / metabolism, MESH: Cerebellar Diseases / genetics, Mutant, INPP5E, Ciliopathies, MESH: Phosphoric Monoester Hydrolases / metabolism, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cerebellum, MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics, Exome, MESH: Animals, Eye Abnormalities, Genetics (clinical), Exome sequencing, Zebrafish, Genetics, 0303 health sciences, MESH: Exome, MESH: Protein Prenylation, Splice site mutation, ADP-Ribosylation Factors, MESH: ADP-Ribosylation Factors / metabolism, Cilium, MESH: Proteomics, Homozygote, MESH: Genetic Predisposition to Disease, MESH: Kidney Diseases, Cystic / genetics, prenylation, Kidney Diseases, Cystic, Pedigree, Female, MESH: Models, Molecular, MESH: Homozygote, MESH: Abnormalities, Multiple, MESH: Zebrafish Proteins / metabolism, PDE6D, MESH: Pedigree, Protein Prenylation, Biology, MESH: Retina / metabolism, MESH: Zebrafish / abnormalities, Joubert syndrome, Article, Retina, MESH: Zebrafish / genetics, 03 medical and health sciences, MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism, primary cilia, MESH: Cerebellar Diseases / metabolism, Cerebellar Diseases, medicine, Animals, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, MESH: Retina / abnormalities, MESH: Eye Abnormalities / metabolism, Cilia, 030304 developmental biology, Cyclic Nucleotide Phosphodiesterases, Type 6, MESH: Humans, Sequence Analysis, DNA, Zebrafish Proteins, medicine.disease, MESH: Cerebellum / abnormalities, Phosphoric Monoester Hydrolases, MESH: Male, MESH: Phosphoric Monoester Hydrolases / genetics, MESH: Eye Abnormalities / genetics, Protein prenylation, MESH: Zebrafish Proteins / genetics, MESH: Female, 030217 neurology & neurosurgery, MESH: Kidney Diseases, Cystic / metabolism
Abstract: International audience; Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.
Published: 2014

35. Trembler as a Mouse Model of CMT1A?

Author: Anja Knoll, Claude Cassagne, Jacques Bonnet, Jérôme Salles, Françoise Boiron-Sargueil, Bertrand Garbay, Anthony M. Heape, Unité de Nutrition Humaine (UNH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université
Subjects: Heterozygote, MESH: Myelin Sheath, [SDV]Life Sciences [q-bio], Mutant, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Mice, Mice, Neurologic Mutants, 03 medical and health sciences, Myelin, 0302 clinical medicine, History and Philosophy of Science, Charcot-Marie-Tooth Disease, MESH: Charcot-Marie-Tooth Disease, medicine, Animals, Humans, MESH: Myelin Proteins, MESH: Animals, MESH: Mice, Gene, Myelin Sheath, MESH: Heterozygote, MESH: Mice, Neurologic Mutants, 030304 developmental biology, Regulation of gene expression, Genetics, 0303 health sciences, Mutation, MESH: Humans, General Neuroscience, Homozygote, Heterozygote advantage, Trembler, biology.organism_classification, MESH: Gene Expression Regulation, Cell biology, Disease Models, Animal, medicine.anatomical_structure, Gene Expression Regulation, Peripheral nervous system, MESH: Disease Models, Animal, Myelin Proteins, 030217 neurology & neurosurgery, MESH: Homozygote
Abstract: International audience; The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.; La souris Trembler souffre d'une mutation autosomique héréditaire dominante qui se traduit par une myélinisation anormale du système nerveux périphérique. Des études biochimiques ont montré que la dysmyélinisation est l'événement principal, la démyélinisation étant un processus tardif. L'expression des gènes de la protéine de la myéline a été étudiée. Les taux d'ARNm de PMP22 à l'état d'équilibre représentent respectivement 10 et 5 % des valeurs normales dans les nerfs des Trembleurs hétérozygotes et homozygotes. Ceci est dû à une expression réduite du transcrit spécifique piloté par le promoteur 1 du gène PMP22. Les résultats collectifs indiquent que la dysmyélinisation de Trembler n'est pas nécessairement la conséquence d'une accumulation importante de la protéine PMP22 mutée. De plus, il apparaît que la situation chez les Trembleurs est différente de celle rencontrée chez la plupart des patients CMT1A, où un dosage accru du gène PMP22 est responsable de la maladie. Par conséquent, le mutant Trembler n'est peut-être pas un modèle idéal pour cette neuropathie humaine.
Published: 1999

36. Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency

Author: Jean-Luc Pellequer, Jean-François Schved, Tahir Shamsi, P. Aguilar-Martinez, Munira Borhany, Muriel Giansily-Blaizot, Grégory Moulis, H. Boijout, Department of Haematology, Haemostasis & Thrombosis, National Institute of Blood Disease & Bone Marrow Transplantation, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Biochimie et Toxicologie Nucléaire (SBTN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Factor VII Deficiency, 030204 cardiovascular system & hematology, Gene mutation, medicine.disease_cause, MESH: Genotype, Exon, chemistry.chemical_compound, 0302 clinical medicine, Genotype-phenotype distinction, phenotype-genotype relationship, MESH: Child, Medicine, Missense mutation, Pakistan, Child, Promoter Regions, Genetic, Genetics (clinical), Genetics, 0303 health sciences, Mutation, MESH: Asian Continental Ancestry Group, Factor VII, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Homozygote, Hematology, General Medicine, 3. Good health, Phenotype, Hepatocyte Nuclear Factor 4, MESH: Young Adult, Child, Preschool, Female, MESH: Hepatocyte Nuclear Factor 4, MESH: Pakistan, MESH: Factor VII, MESH: Homozygote, Protein Binding, Adolescent, Genotype, Mutation, Missense, Consanguinity, MESH: Phenotype, 03 medical and health sciences, Young Adult, Asian People, MESH: Promoter Regions, Genetic, MESH: Protein Binding, Humans, FVII deficiency, Gene, rare bleeding disorder, Alleles, 030304 developmental biology, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, Binding Sites, business.industry, MESH: Alleles, MESH: Child, Preschool, MESH: Male, chemistry, MESH: Binding Sites, MESH: Factor VII Deficiency, mutation, business, MESH: Female
Abstract: International audience; Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series.
Published: 2013

37. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis

Author: André Mégarbané, Cécile Laroche, Isabelle Marty, Klaus Dieterich, Nicole Monnier, Damien Sternberg, Pierre-Simon Jouk, Jie Zhou, Susana Quijano-Roy, Daniela Avila Smirnow, Pascale Marcorelles, Robert Carlier, Sylvie Odent, Brigitte Estournet, Julien Fauré, Norma B. Romero, Sandra Mercier, Judith Melki, Joël Lunardi, INSERM U836, équipe 4, Muscles et pathologies, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Génétique et Procréation, CHU Grenoble-CHU Grenoble-Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant-Hôpital Couple Enfant, Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie Génétique et Moléculaire, CHU Grenoble-Institut de Biologie et de Pathologie (IBP)-CHU Grenoble-Institut de Biologie et de Pathologie (IBP), Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant, Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Anatomopathologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique et Procréation, CHU Grenoble, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Pyopathies, PHRC (AOM 10181), Inserm, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Roux-Buisson, Nathalie
Subjects: Central Nervous System, Pathology, Genetic Linkage, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Compound heterozygosity, Endothelins, Consanguinity, Mice, 0302 clinical medicine, MESH: Embryonic Development, MESH: Animals, 10. No inequality, Genetics (clinical), Arthrogryposis, Motor Neurons, 0303 health sciences, Mutation, Homozygote, Chromosome Mapping, Metalloendopeptidases, General Medicine, Anatomy, Muscle atrophy, 3. Good health, Pedigree, Phenotype, medicine.symptom, MESH: Motor Neurons, MESH: Homozygote, medicine.hormone, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, MESH: Arthrogryposis, MESH: Genetic Linkage, MESH: Metalloendopeptidases, Embryonic Development, Genes, Recessive, Biology, MESH: Phenotype, 03 medical and health sciences, Genetics, medicine, MESH: Central Nervous System, Animals, Humans, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Muscle contracture, MESH: Consanguinity, [SDV.GEN]Life Sciences [q-bio]/Genetics, Arthrogryposis multiplex congenita, MESH: Humans, Heterozygote advantage, MESH: Chromosome Mapping, 030217 neurology & neurosurgery
Abstract: International audience; Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes. Using a pangenomic approach, we demonstrated linkage of DA to chromosome 2q37 in two consanguineous families and the endothelin-converting enzyme like 1 (ECEL1) gene present in this region was associated with DA. Screening of a panel of 20 families with non-specific DA identified seven homozygous or compound heterozygous mutations of ECEL1 in a total of six families. Mutations resulted mostly in the absence of protein. ECEL1 is a neuronal endopeptidase predominantly expressed in the central nervous system and brain structures during fetal life in mice and human. ECEL1 plays a major role in intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis. A detailed review of clinical findings of DA patients with ECEL1 mutations revealed a homogeneous and recognizable phenotype characterized by limited knee flexion, flexed third to fifth fingers and severe muscle atrophy predominant on lower limbs and tongue that suggested a common pathogenic mechanism. We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction.
Published: 2012

38. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis

Author: Gérard Orth, Luz-Stella Montoya, Bakar Bouadjar, Luis-Alfredo Rueda, Nicolas Ramoz, Michel Favre, Papillomavirus, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unidad Dermatológica L-A Rueda, Unidad Dermatológica L-A Rueda, Bogotá, Colombia., Centre Hospitalier Universitaire de Bab-el-Oued, Centre Hospitalier Universitaire de Bab-el-Oued, Alger, Algérie., Universidad Industrial de Santander [Bucaramanga] (UIS), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, TMC6, Amino Acid Motifs, DNA Mutational Analysis, MESH: Amino Acid Sequence, MESH: Genetic Markers, MESH: Base Sequence, Endoplasmic Reticulum, MESH: Amino Acid Motifs, MESH: Protein Structure, Tertiary, 030207 dermatology & venereal diseases, 0302 clinical medicine, MESH: Codon, Nonsense, MESH: DNA Mutational Analysis, Conserved Sequence, Recombination, Genetic, Genetics, 0303 health sciences, MESH: Conserved Sequence, Homozygote, MESH: Genetic Predisposition to Disease, Exons, MESH: Epidermodysplasia Verruciformis, Pedigree, 3. Good health, Codon, Nonsense, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, MESH: Recombination, Genetic, MESH: Membrane Proteins, MESH: Homozygote, Genetic Markers, MESH: Pedigree, Molecular Sequence Data, Nonsense mutation, MESH: Sequence Alignment, Biology, 03 medical and health sciences, MESH: Endoplasmic Reticulum, medicine, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Gene, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Genodermatosis, Membrane Proteins, Chromosome, MESH: Haplotypes, Epidermodysplasia verruciformis, medicine.disease, MESH: Male, Protein Structure, Tertiary, Haplotypes, Epidermodysplasia Verruciformis, MESH: Microsatellite Repeats, TMC8, MESH: Exons, Skin Carcinoma, Sequence Alignment, MESH: Female, MESH: Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 17, Microsatellite Repeats
Abstract: Epidermodysplasia verruciformis (OMIM 226400) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses (HPVs). We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17q25. Here we report the identification of nonsense mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with the disease. The gene products EVER1 and EVER2 have features of integral membrane proteins and are localized in the endoplasmic reticulum.
Published: 2002

39. Peroxisome Proliferator-Activated Receptor-alpha Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Author: Kristiaan Wouters, Jonathan Vanhoutte, Morgane Baron, Fanny Lalloyer, Bart Staels, Sandrine Caron, Ronit Shiri-Sverdlov, Marten H. Hofker, Emmanuelle Vallez, Eric Baugé, Anne Tailleux, Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Molecular Genetics, Nutrition and Toxicology Research and Cardiovascular Research (NUTRIM & CARIM), Institutes of Maastricht, Department of Medical Biology, University of Groningen [Groningen], Derudas, Marie-Hélène, RS: NUTRIM - R2 - Gut-liver homeostasis, and Moleculaire Genetica
Subjects: MESH: Inflammation, Apolipoprotein B, Apolipoprotein E2, PPARalpha, Anti-Inflammatory Agents, Peroxisome proliferator-activated receptor, 030204 cardiovascular system & hematology, MOUSE, MESH: Mice, Knockout, DEFICIENT MICE, MESH: Atherosclerosis, murine model, STEATOHEPATITIS, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, PPAR-ALPHA, lipid metabolism, MESH: Animals, Gene Knock-In Techniques, MESH: Hypolipidemic Agents, MESH: PPAR alpha, Receptor, MESH: Apolipoprotein E2, MESH: Fatty Liver, Aorta, MESH: Gene Knock-In Techniques, Hypolipidemic Agents, MESH: Heterozygote, MESH: Lipid Metabolism, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, Fenofibrate, Homozygote, Fatty liver, food and beverages, MESH: Aorta, Lipids, MESH: Gene Expression Regulation, AGONIST, Liver, CARDIOVASCULAR-DISEASE, cardiovascular system, Female, lipids (amino acids, peptides, and proteins), FENOFIBRATE, Peroxisome proliferator-activated receptor alpha, Cardiology and Cardiovascular Medicine, MESH: Homozygote, medicine.drug, Heterozygote, medicine.medical_specialty, MESH: Mice, Transgenic, Mice, Transgenic, Biology, digestive system, Article, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Analysis of Variance, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, PPAR alpha, MESH: Mice, 030304 developmental biology, FATTY LIVER-DISEASE, Analysis of Variance, MESH: Humans, nutritional and metabolic diseases, Lipid metabolism, GAMMA, MESH: Fenofibrate, medicine.disease, Atherosclerosis, MESH: Lipids, Fatty Liver, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Gene Expression Regulation, chemistry, inflammation, MESH: Anti-Inflammatory Agents, biology.protein, fatty liver disease, MESH: Disease Models, Animal, Steatohepatitis, MESH: Female, MESH: Liver
Abstract: Objective— Peroxisome proliferator–activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Methods and Results— Wild-type (+/+), heterozygous (+/−), and homozygous (−/−) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet–fed PPARα−/− apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/− apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/− apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/−, and PPARα−/− apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. Conclusion— These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
Published: 2011

40. Determination of exon 7 SMN1 deletion in Iranian patients and heterozygous carriers by quantitative real-time PCR

Author: Mehrdad Noruzinia, Mohammad Hamid, Hossein Mozdarani, Mohammad Esmaeil Akbari, Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University [Tehran], Tehran Medical Genetics Laboratory, Tehran Medical Genetics Laboratory [Iran], Molecular Medicine Division, Biotechnology Research Center, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported in part by Tarbiat Modares University through Research Grant allocated to MTA, and The authors appreciate the collaboration of patients and their families as well as their clinicians. We thank the staff of Tehran Medical Genetics Laboratory especially Mrs S. Zare and Dr Karimipoorfor their valuable contributions.
Subjects: Heterozygote, education, SMN1, Biology, Compound heterozygosity, Polymerase Chain Reaction, Muscular Atrophy, Spinal, 03 medical and health sciences, Exon, MESH: Muscular Atrophy, Spinal, MESH: Survival of Motor Neuron 1 Protein, Genetics, Paralysis, medicine, otorhinolaryngologic diseases, Humans, SMNI gene, 030304 developmental biology, Sequence Deletion, spinal muscular atrophy, MESH: Heterozygote, 0303 health sciences, MESH: Humans, MESH: Heterozygote Detection, Genetic Carrier Screening, 030305 genetics & heredity, Homozygote, MESH: Polymerase Chain Reaction, Spinal muscular atrophy, Exons, Motor neuron, MESH: Sequence Deletion, medicine.disease, Spinal cord, SMA, Molecular biology, Survival of Motor Neuron 1 Protein, humanities, 3. Good health, nervous system diseases, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, exon 7 detection, medicine.symptom, real-time PCR, MESH: Exons, geographic locations, MESH: Homozygote
Abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the degeneration of motor neurons of the spinal cord anterior horns, leading to progressive atrophy of proximal muscles, paralysis, respiratory failure, and even infant death. Patients with SMA are classified into three types, based on the age at onset and clinical severity (Munsat and Davies 1992; Wirth et al. 1995): type I (MIM 253300) is the most severe form, type II (MIM 253550) is the intermediate form, and type III (MIM 253400) is the mildest form. With an incidence of 1/6000 to 1/10000 and a carrier frequency of 1/40 to 1/50, SMA is the second most frequent autosomal recessive disease in Europeans (Pearn 1980). The SMA determining gene called the ‘survival motor neuron’ gene (SMN) is present on 5q13 in two copies, SMN1 and SMN2, which differ by only five nucleotide exchanges within their 3′ ends (Lefebvre et al. 1995). Two of these base-pair exchanges, located in exons 7 and 8 (which allow SMN1 to be distinguished from SMN2) currently are used for direct diagnosis of SMA. Therefore, the first step in this test is to amplify specifically SMN1 exon 7 or exon 8 and later on subjecting the PCR product to restriction digestion, a PCR-RFLP approach (Scheffer et al. 2001). In a study of 1122 patients with type I, type II, or type III SMA it was shown that in about 94% of SMA patients (in all three types) homozygous absence of SMN1 is responsible for this disease (Scheffer et al. 2000). Approximately half of the remaining patients were identified as compound heterozygote (with deletions and intragenic SMN1mutations), whereas the other half, without SMN1 mutations, were considered as distinct genetic entities (Wirth et al. 1999). The carrier test for
Published: 2011

41. Functional assays to determine the significance of two common XPC 3'UTR variants found in bladder cancer patients

Author: Anne E. Kiltie, Johanne Bentley, Laurence Vaslin, Margaret A. Knowles, Gina B. Scott, Faye Elliott, D T Bishop, Janet Hall, Boling Qiao, Section of Experimental Oncology, Leeds Institute of Molecular Medicine, Section of Epidemiology and Biostatistics, Génotoxicologie, signalisation et radiothérapie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Department of Oncology, University of Oxford [Oxford]-Gray Institute for Radiation Oncology and Biology, This work was supported by Cancer Research UK [C6228/A7625, C15140/A7298 and C5255/A12678, AEK] and Yorkshire Cancer Research [L304, AEK]., Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford-Gray Institute for Radiation Oncology and Biology, and BMC, Ed.
Subjects: Linkage disequilibrium, Transcription, Genetic, RNA Stability, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Genetics(clinical), 3' Untranslated Regions, Genetics (clinical), 0303 health sciences, MESH: Polymorphism, Single Nucleotide, Homozygote, MESH: RNA Stability, MESH: 3' Untranslated Regions, 3. Good health, MESH: Urinary Bladder Neoplasms, DNA-Binding Proteins, 030220 oncology & carcinogenesis, MESH: Protein Biosynthesis, Research Article, MESH: Homozygote, lcsh:Internal medicine, medicine.medical_specialty, lcsh:QH426-470, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, medicine, Humans, RNA, Messenger, Allele, lcsh:RC31-1245, Alleles, Carcinogen, 030304 developmental biology, MESH: RNA, Messenger, Messenger RNA, Bladder cancer, MESH: Humans, Three prime untranslated region, MESH: Alleles, MESH: Transcription, Genetic, Cytogenetics, medicine.disease, Molecular biology, MESH: Cell Line, lcsh:Genetics, Urinary Bladder Neoplasms, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, MESH: DNA-Binding Proteins, Nucleotide excision repair
Abstract: Background XPC is involved in the nucleotide excision repair of DNA damaged by carcinogens known to cause bladder cancer. Individuals homozygous for the variant allele of XPC c.1496C > T (p.Ala499Val) were shown in a large pooled analysis to have an increased bladder cancer risk, and we found two 3'UTR variants, *611T > A and c.*618A > G, to be in strong linkage disequilibrium with c.1496T. Here we determined if these two 3'UTR variants can affect mRNA stability and assessed the impact of all three variants on mRNA and protein expression. Methods In vitro mRNA stability assays were performed and mRNA and protein expression measured both in plasmid-based assays and in lymphocytes and lymphoblastoid cell lines from bladder and breast cancer patients. Results The two 3'UTR variants were associated with reduced protein and mRNA expression in plasmid-based assays, suggesting an effect on mRNA stability and/or transcription/translation. A near-significant reduction in XPC protein expression (p = 0.058) was detected in lymphoblastoid cell lines homozygous for these alleles but no differences in mRNA stability in these lines was found or in mRNA or protein levels in lymphocytes heterozygous for these alleles. Conclusion The two 3'UTR variants may be the variants underlying the association of c.1496C > T and bladder cancer risk acting via a mechanism modulating protein expression.
Published: 2011

42. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Author: Vaysse, A., Ratnakumar, A., Derrien, T., Axelsson, E., Rosengren Pielberg, G., Sigurdsson, S., Fall, T., Seppälä, E.H., Hansen, M.S., Lawley, C.T., Karlsson, E.K., Bannasch, D.L., Vilà, C., Lohi, H., Galibert, F., Fredholm, M., Häggström, O., Hedhammar, A., André, C., Lindblad-Toh, K., Hitte, C., van Steenbeek, F.G., Fieten, H., Leegwater, P.A.J., LUPA Consortium, x, Webster, M.T., Advances in Veterinary Medicine, Tissue Repair, Geneeskunde van gezelschapsdieren, Research Programs Unit, Department of Medical and Clinical Genetics, Research Programme of Molecular Medicine, Veterinary Biosciences, Departments of Faculty of Veterinary Medicine, Broad Institute of MIT and Harvard, Sigurdsson, Snaever, Sigurdsson, Snaevar, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Webster, Matthew T., Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Science for Life Laboratory, Uppsala University-Department of Medical Biochemistry and Microbiology, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Department of Basic Veterinary Biosciences, HMNC Brain Health-Biomedicum Helsinki-Folkhälsan Institute of Genetics, Illumina, Inc., FAS Center for Systems Biology, Harvard University [Cambridge], Department of Population Health and Reproduction, University of California [Davis] (UC Davis), University of California-University of California, Department of Integrative Ecology (CSIC), Estación Biológica de Doñana (EBD), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Faculty of Life Sciences, Division of Genetics and Bioinformatics, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Swedish University of Agricultural Sciences (SLU), This research was mainly supported by The LUPA Consortium, which is a Collaborative Research Project funded by the European Commission under the 7th Research Framework Programme (www.eurolupa.org)., The LUPA Consortium, European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Harvard University, University of California (UC)-University of California (UC), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), De Villemeur, Hervé, and Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID
Subjects: POSITIVE SELECTION, Genotyping Techniques, Genome-wide association study, Breeding, 413 Veterinary science, MESH: Dogs, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Genome Sequencing, MESH: Genetic Variation, mapping, MESH: Phylogeny, Genome Evolution, Phylogeny, 0303 health sciences, education.field_of_study, Behavior, Animal, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, Genomics, Genome Scans, selection, dog, identification, genomic, Fixation (population genetics), COAT COLOR, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], PERSONALITY-TRAITS, Gene Flow, Genetics and Breeding, education, Single-nucleotide polymorphism, MESH: Breeding, MESH: Phenotype, 03 medical and health sciences, CANIS-FAMILIARIS, Effective Population Size, MESH: Genotyping Techniques, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genome-Wide Association Studies, Genetics, Genetik, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic Drift, MESH: Ear, Computational Biology, Genetic Variation, MESH: Haplotypes, Phenotypic trait, HAPLOTYPE STRUCTURE, variation phénotypique, Mutation, MESH: Genome-Wide Association Study, marqueur de sélection, Population Genetics, 030217 neurology & neurosurgery, Evolutionary Genetics, Cancer Research, cartographie génomique, LINKAGE DISEQUILIBRIUM, MESH: Selection, Genetic, [SDV.GEN] Life Sciences [q-bio]/Genetics, Natural Selection, Body Size, WIDE ASSOCIATION, Genetics (clinical), DOMESTIC DOG, MESH: Heterozygote, Gene Ontologies, Homozygote, race canine, 402 Animal and Dairy Science, Ear, Gene Pool, Phenotype, Research Article, MESH: Homozygote, Heterozygote, 403 Veterinary Science, lcsh:QH426-470, Population, Polymorphism, Single Nucleotide, Dogs, Genetic drift, Genome Analysis Tools, DNA-SEQUENCE, Evolutionary Modeling, Genetic variation, Animals, Selection, Genetic, Selection (genetic algorithm), 030304 developmental biology, Evolutionary Biology, MESH: Body Size, Genetic Maps, Comparative Genomics, GENE, lcsh:Genetics, Haplotypes, Neutral Theory, Genetic Polymorphism, Animal Genetics, Genome-Wide Association Study
Abstract: The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of .170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.
Published: 2011

43. Four-Year Follow-up of Diagnostic Service in USH1 Patients

Author: Muriel Holder-Espinasse, Albert David, Brigitte Gilbert-Dussardier, Michel Mondain, Mireille Claustres, Christel Vaché, Anne Francoise Roux, Christian P. Hamel, Sue Malcolm, Geneviève Lina-Granade, Didier Lacombe, Umberto Ambrosetti, Thomas Besnard, Susana Léonard, Dominique Bonneau, Catherine Blanchet, Hubert Journel, Valérie Faugère, Patrick Edery, David Baux, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service ORL, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), GENDEV Team [Bron], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Milano [Milano] (UNIMI), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'ORL, chirurgie cervico-maxillo-faciale et d'audiophonologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Clinical and Molecular Genetics, University College of London [London] (UCL)-Institute of Child Health, Supported in part by le Ministère de la Recherche 'PHRC (Le Programme Hospitalier de Recherche Clinique) National 2004, PROM 7802,' AG2R Foundation, and SOS Rétinite., and The authors thank the families who participated in this study and Clarisse Baumann, Maria Bitner-Glindzicz, Patricia Blanchet, Pierangela Castorina, Christine Francannet, Anne-Marie Frances, Alice Goldenberg, Georges Haddad, Koenraad Devriendt, Sandrine Marlin, Dominique Martin-Coignard, Philippe Parent, Annick Rossi, Sabine Sigaudy, Renaud Touraine, Annick Toutain, and Jacqueline Vigneron for referring patients and Philippe Khau Van Kien and Christophe Béroud for initial design of the CGH array.
Subjects: DNA Mutational Analysis, medicine.disease_cause, Cohort Studies, MESH: Genotype, 0302 clinical medicine, Genotype, Missense mutation, MESH: DNA Mutational Analysis, MESH: Cohort Studies, Genetics, 0303 health sciences, Mutation, medicine.diagnostic_test, MESH: Genetic Testing, Homozygote, MESH: Genetic Heterogeneity, Chromosome Mapping, MESH: Follow-Up Studies, MESH: Usher Syndromes/genetics, 3. Good health, Myosin VIIa, France, Usher Syndromes, MESH: Homozygote, Mutation, Missense, Myosins, Biology, Genetic Heterogeneity, 03 medical and health sciences, medicine, Humans, MESH: Myosin VIIa, MESH: Usher Syndromes/classification, Genetic Testing, Multiplex ligation-dependent probe amplification, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Gene, 030304 developmental biology, Genetic testing, MESH: Mutation, Missense, MESH: Humans, Genetic heterogeneity, Haplotype, MESH: Haplotypes, MESH: Myosins/genetics, MESH: France, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Mutation, MESH: Usher Syndromes/diagnosis, MESH: Chromosome Mapping, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; PURPOSE: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes.METHODS: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements.RESULTS: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene.CONCLUSIONS: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.
Published: 2011

44. The genome of Theobroma cacao

Author: Zi Shi, Thierry Legavre, Jean-Marc Aury, Joseph Moroh Akaza, Jetty S.S. Ammiraju, Claire Lanaud, Ronan Rivallan, Olivier Panaud, Spencer Brown, Valentin Guignon, Stéphanie Bocs, Jose Fernandes Barbosa-Neto, Zhaorong Ma, Xiang Song, Ismael S. Kébé, Christopher Viot, Melissa Kramer, Jérôme Gouzy, Aurélie Bérard, John E. Carlson, Florent Murat, Manuel Ruiz, Didier Clément, François Sabot, Bertrand Pitollat, Dominique Brunel, Michel Boccara, W. Richard McCombie, Xavier Sabau, Stephan C. Schuster, Francis Quetier, Gaëtan Droc, Yufan Zhang, Thomas Schiex, Anne Dievart, Karina Peres Gramacho, Julie Poulain, Wolfgang Golser, Mickael Bourge, Mark J. Guiltinan, Yolande Roguet, Rod A. Wing, Cristian Chaparro, Olivier Fouet, Xavier Argout, Siela N. Maximova, Jérôme Salse, Michael J. Axtell, Pierre Costet, Mathias Tahi, Dave Kudrna, Emmanuel Guiderdoni, Erika Sallet, Laura Gelley, Ange-Marie Risterucci, Diógenes Infante, Patrick Wincker, Mathilde Allègre, Michael Abrouk, Maguy Rodier-Goud, Angélique D'Hont, Génétique Diversité et Ecophysiologie des Céréales (GDEC), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Biodiversité, Gènes & Communautés (BioGeCo), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ecology and Evolutionary Biology [Tucson] (EEB), University of Arizona, Institut National de la Recherche Agronomique (INRA), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Cold Spring Harbor Laboratory (CSHL), Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Polymorphismes d'intérêt agronomique (UMR PIA), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Etude du Polymorphisme des Génomes Végétaux (EPGV), Animalerie spécialisée, Université Bordeaux Segalen - Bordeaux 2, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: 0106 biological sciences, MESH: Genome, Plant, Theobroma, MESH: Cacao, 01 natural sciences, Genome, F30 - Génétique et amélioration des plantes, MESH: Genotype, Gene Expression Regulation, Plant, MESH: Genes, Plant, cocoa statistics, MESH: Models, Genetic, MESH: Evolution, Molecular, In Situ Hybridization, 2. Zero hunger, Genetics, cacaoyer, 0303 health sciences, biology, Homozygote, MESH: DNA, F70 - Taxonomie végétale et phytogéographie, Cacao tree, MESH: DNA Transposable Elements, Genome, Plant, MESH: Homozygote, MESH: Cell Nucleus, Genotype, Quantitative Trait Loci, Moniliophthora, Genes, Plant, Evolution, Molecular, 03 medical and health sciences, MESH: In Situ Hybridization, Gene family, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Theobroma cacao, MESH: Gene Expression Regulation, Plant, Genome size, Gene, 030304 developmental biology, Cell Nucleus, Cacao, Models, Genetic, Chromosome, DNA, biology.organism_classification, MESH: Quantitative Trait Loci, DNA Transposable Elements, cacao genome, 010606 plant biology & botany
Abstract: International audience; We sequenced and assembled the draft genome of Theobroma cacao, an economically important tropical-fruit tree crop that is the source of chocolate. This assembly corresponds to 76% of the estimated genome size and contains almost all previously described genes, with 82% of these genes anchored on the 10 T. cacao chromosomes. Analysis of this sequence information highlighted specific expansion of some gene families during evolution, for example, flavonoid-related genes. It also provides a major source of candidate genes for T. cacao improvement. Based on the inferred paleohistory of the T. cacao genome, we propose an evolutionary scenario whereby the ten T. cacao chromosomes were shaped from an ancestor through eleven chromosome fusions.
Published: 2010

45. B-raf alternative splicing is dispensable for development but required for learning and memory associated with the hippocampus in the adult mouse

Author: Alain Eychène, Agathe Valluet, Magalie Larcher, Sabrina Davis, Sabine Druillennec, Isabelle Hmitou, Serge Laroche, Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Neurosciences Paris-Sud (CNPS), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Hippocampus, Mouse, MESH: Myelin Sheath, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, MESH: Fear, lcsh:Medicine, Signal transduction, ERK signaling cascade, Hippocampus, MESH: Mice, Knockout, Gene Splicing, Exon, Mice, Behavioral Neuroscience, 0302 clinical medicine, Molecular cell biology, Learning and Memory, Conditional gene knockout, Signaling in Cellular Processes, MESH: Animals, MESH: Memory, MESH: Phylogeny, lcsh:Science, Myelin Sheath, Phylogeny, Regulation of gene expression, Genetics, Mice, Knockout, 0303 health sciences, Multidisciplinary, Animal Behavior, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Alternative Splicing, Homozygote, Signaling cascades, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Exons, Fear, Animal Models, MESH: Gene Expression Regulation, RNA splicing, Research Article, MESH: Homozygote, Gene isoform, Proto-Oncogene Proteins B-raf, MAPK signaling cascades, DNA transcription, Ras Signaling, Biology, 03 medical and health sciences, Model Organisms, Memory, Animals, Learning, Gene, MESH: Mice, 030304 developmental biology, Evolutionary Biology, MESH: Proto-Oncogene Proteins B-raf, Evolutionary Developmental Biology, Alternative splicing, lcsh:R, Alternative Splicing, Protein kinase domain, Gene Expression Regulation, RNA processing, NIH 3T3 Cells, MESH: Learning, lcsh:Q, Gene Function, MESH: Exons, Animal Genetics, 030217 neurology & neurosurgery, Developmental Biology, Neuroscience, MESH: NIH 3T3 Cells
Abstract: International audience; The B-raf proto-oncogene exerts essential functions during development and adulthood. It is required for various processes, such as placental development, postnatal nervous system myelination and adult learning and memory. The mouse B-raf gene encodes several isoforms resulting from alternative splicing of exons 8b and 9b located in the hinge region upstream of the kinase domain. These alternative sequences modulate the biochemical and biological properties of B-Raf proteins. To gain insight into the physiological importance of B-raf alternative splicing, we generated two conditional knockout mice of exons 8b and 9b. Homozygous animals with a constitutive deletion of either exon are healthy and fertile, and survive up to 18 months without any visible abnormalities, demonstrating that alternative splicing is not essential for embryonic development and brain myelination. However, behavioural analyses revealed that expression of exon 9b-containing isoforms is required for B-Raf function in hippocampal-dependent learning and memory. In contrast, mice mutated on exon 8b are not impaired in this function. Interestingly, our results suggest that exon 8b is present only in eutherians and its splicing is differentially regulated among species.
Published: 2010

46. Comparative assessment of methods for estimating individual genome-wide homozygosity-by-descent from human genomic data

Author: Ruth McQuillan, Alan F. Wright, James F. Wilson, Anne-Louise Leutenegger, Céline Bellenguez, Ozren Polasek, Igor Rudan, Veronique Vitart, Caroline Hayward, Ulf Gyllensten, Ivana Kolcic, Vanja Saftić, Harry Campbell, Public Health Sciences, University of Edinburgh, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Human Genetics Unit, Medical Research Council, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Sestre Milosrdnice, Department of Genetics and Pathology, Rudbeck Laboratory, Gen-info d.o.o., Croatian Centre for Global Health, University of Split, OP was supported by the Public Health Sciences University of Edinburgh PhD Scholarship and the Overseas Research Support Scheme, as well as postgraduate scholarship from the Ministry of Science, Education and Sports of the Republic of Croatia. This study was supported through the grants from the Medical Research Council UK to AFW, HC and IR and the Ministry of Science, Education and Sport of the Republic of Croatia to IR (number 216-1080315-0302)., and BMC, Ed.
Subjects: Linkage disequilibrium, lcsh:QH426-470, Genotype, Croatia, lcsh:Biotechnology, Inheritance Patterns, Single-nucleotide polymorphism, Computational biology, Biology, Genome, Polymorphism, Single Nucleotide, Correlation, MESH: Genotype, 03 medical and health sciences, Consanguinity, MESH: Computer Simulation, lcsh:TP248.13-248.65, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, SNP, Humans, Computer Simulation, Genetic Association Studies, MESH: Genome, Human, 030304 developmental biology, MESH: Genetic Association Studies, MESH: Consanguinity, 0303 health sciences, Likelihood Functions, MESH: Humans, Genome, Human, MESH: Polymorphism, Single Nucleotide, 030305 genetics & heredity, Homozygote, Genome-wide homozygosity, heterozygosity, inbreeding, lcsh:Genetics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Human genome, MESH: Likelihood Functions, MESH: Inheritance Patterns, Inbreeding, MESH: Croatia, Research Article, Biotechnology, MESH: Homozygote
Abstract: Background Genome-wide homozygosity estimation from genomic data is becoming an increasingly interesting research topic. The aim of this study was to compare different methods for estimating individual homozygosity-by-descent based on the information from human genome-wide scans rather than genealogies. We considered the four most commonly used methods and investigated their applicability to single-nucleotide polymorphism (SNP) data in both a simulation study and by using the human genotyped data. A total of 986 inhabitants from the isolated Island of Vis, Croatia (where inbreeding is present, but no pedigree-based inbreeding was observed at the level of F > 0.0625) were included in this study. All individuals were genotyped with the Illumina HumanHap300 array with 317,503 SNP markers. Results Simulation data suggested that multi-point FEstim is the method most strongly correlated to true homozygosity-by-descent. Correlation coefficients between the homozygosity-by-descent estimates were high but only for inbred individuals, with nearly absolute correlation between single-point measures. Conclusions Deciding who is really inbred is a methodological challenge where multi-point approaches can be very helpful once the set of SNP markers is filtered to remove linkage disequilibrium. The use of several different methodological approaches and hence different homozygosity measures can help to distinguish between homozygosity-by-state and homozygosity-by-descent in studies investigating the effects of genomic autozygosity on human health.
Published: 2010

47. Screening for new mutations in the LDL receptor gene in seven French familial hypercholesterolemia families by the single strand conformation polymorphism method

Author: Catherine Boileau, N. Loux, B. Saint-Jore, F. Dairou, Truffert J, J. L. de Gennes, Claudine Junien, P. Douste-Blazy, B. Dastugue, Benlian P, G. Collod, Génétique et pathologie fœtale, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHR Clermont-Ferrand, CHU Clermont-Ferrand, Biochimie des Lipides, and COLLOD-BEROUD, Gwenaëlle
Subjects: Male, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, Familial hypercholesterolemia, MESH: Base Sequence, 030204 cardiovascular system & hematology, Compound heterozygosity, medicine.disease_cause, Polymerase Chain Reaction, Exon, 0302 clinical medicine, Missense mutation, MESH: DNA Mutational Analysis, Promoter Regions, Genetic, Genetics (clinical), MESH: Heterozygote, Genetics, 0303 health sciences, Mutation, Homozygote, MESH: DNA, Exons, Pedigree, 3. Good health, MESH: Hyperlipoproteinemia Type II, MESH: DNA Probes, MESH: Polymo, Female, France, DNA Probes, MESH: Homozygote, Heterozygote, MESH: Pedigree, Molecular Sequence Data, Nonsense mutation, Biology, Hyperlipoproteinemia Type II, 03 medical and health sciences, medicine, Humans, Point Mutation, Amino Acid Sequence, MESH: Point Mutation, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Polymerase Chain Reaction, Single-strand conformation polymorphism, DNA, medicine.disease, Molecular biology, MESH: Male, MESH: France, Receptors, LDL, LDL receptor, MESH: Exons, MESH: Female
Abstract: To investigate the molecular basis of familial hypercholesterolemia (FH) in France, we applied the single strand conformation polymorphism (SSCP) method to the promoter region and the 18 exons of the low density lipoprotein receptor (LDLR) gene. Seven probands, 4 heterozygotes, 2 compound heterozygotes, and 1 homozygote, belonging to FH families were tested. In all cases, previous genetic analysis and/or LDL receptor fibroblast assay had shown that the disease was due to defects in the LDLR gene. Out of the nine mutations expected, one nonsense mutation in exon 2 and six missense mutations were identified in exons 3, 6, 8, 11, and 15. Two of the latter were found in exon 6. In each family, cosegregation of the base substitution and the disease was observed. Ninety-five control subjects were screened for the presence of the six missense mutations. None was detected, implying that the mutations identified are deleterious. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used to rapidly screen mutation containing exons in large genes. Furthermore, all these mutations are newly described and demonstrate heterogeneity of LDLR gene mutations responsible for FH in the French population, as in other reported Caucasian populations. © 1992 Wiley-Liss, Inc.
Published: 1992

48. Factor v Leiden homozygous genotype and pregnancy outcomes

Author: Anne Bauters, Catherine Saladin-Thiron, Agnès Lequerrec, Fabienne Dutrillaux, Benoit Polack, B. Delahousse, Véronique Le Cam-Duchez, Catherine Boinot, Christine Biron-Andreani, Yves Gruel, Pierre-Emmanuel Morange, Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire d'Hématologie-Hémostase, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 030204 cardiovascular system & hematology, MESH: Factor V, Cohort Studies, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH: Embryo Loss, MESH: Cohort Studies, MESH: Heterozygote, 030219 obstetrics & reproductive medicine, MESH: Middle Aged, biology, Homozygote, Factor V, Pregnancy Outcome, Obstetrics and Gynecology, Middle Aged, Embryo Loss, Gestation, Female, France, Cohort study, MESH: Homozygote, Adult, medicine.medical_specialty, Heterozygote, Homozygous genotype, Thrombophilia, 03 medical and health sciences, Factor V Leiden, medicine, Humans, Pregnancy outcomes, Fetal Death, Retrospective Studies, Gynecology, MESH: Humans, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, Odds ratio, medicine.disease, MESH: Pregnancy Outcome, MESH: France, biology.protein, MESH: Fetal Death, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; OBJECTIVE: To assess the rate of early (first trimester) and late (second and third trimester) fetal loss in women who are factor V Leiden homozygous. METHODS: Between December 1995 and February 2007, consecutive, unrelated white women who were factor V Leiden homozygous and who had been pregnant at least once were recruited from 10 French hemostasis units. For reasons of comparison, we included women who were factor V Leiden heterozygous and a group of noncarriers. The frequency of early and late fetal loss was assessed retrospectively and compared among the three groups. The effect of concomitant thrombophilic abnormalities was evaluated. The overall pregnancy outcome was reported. RESULTS: We analyzed 240 thromboprophylaxis-free pregnancies in 95 women who were factor V Leiden homozygous, 425 in 195 women who were factor V Leiden heterozygous, and 182 in 73 women who were noncarriers. The risk of late fetal loss was higher in women who were homozygous (13/95, 13.7%) compared with those who were noncarriers (1/73, 1.4%, odds ratio 11.41, 95% confidence interval 1.46-89.46, P=.002), whereas it was similar in women who were heterozygous and in noncarriers (6/195, 3.1% compared with 1/73, 1.4%, P=.68). The percentage of women with early fetal loss was similar in the three groups (P=.81). The live-birth rate was 80%, 84%, and 85%, respectively, for women who where homozygous, heterozygous, and noncarriers (P=.88). CONCLUSION: The factor V Leiden homozygous genotype increases the risk of late fetal loss. However, the overall likelihood of a positive outcome is high in our series of women who were homozygous. LEVEL OF EVIDENCE: III.
Published: 2009

49. Homogénéité mutationnelle de la glycogénose de type Ia en Tunisie

Author: A. Ben Chehida, Neziha Kaabachi, M. Ben Dridi, Neji Tebib, Sonia Abdelhak, F. Amri, Kamel Monastiri, Wafa Cherif, Hatem Azzouz, Jalel Chemli, F. Ben Rhouma, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Unité de recherche ' Dépistage et de prise en charge des maladies héréditaires du métabolisme ', service de pédiatrie, Hôpital La Rabta [Tunis], Service de pédiatrie, CHU Fattouma Bourguiba [Monastir] (HFB), hôpital Ibn El Jazzar, hôpital Sahloul, and Service de Biochimie
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, MESH: Mutation, Tunisia, Mutant, DNA Mutational Analysis, Diagnosis tool, Hypoglycemia, MESH: Base Sequence, Glycogen Storage Disease Type I, Short stature, Gastroenterology, 03 medical and health sciences, Internal medicine, medicine, Humans, Allele, MESH: DNA Mutational Analysis, 030304 developmental biology, MESH: Heterozygote, 0303 health sciences, MESH: Humans, medicine.diagnostic_test, MESH: Glycogen Storage Disease Type I, Base Sequence, business.industry, 030305 genetics & heredity, Homozygote, MESH: DNA, nutritional and metabolic diseases, General Medicine, DNA, medicine.disease, MESH: Glucose-6-Phosphatase, 3. Good health, Liver, Liver biopsy, Mutation (genetic algorithm), Mutation, Mutation testing, Glucose-6-Phosphatase, medicine.symptom, business, MESH: Tunisia, MESH: Homozygote, MESH: Liver
Abstract: International audience; The glycogen storage disease type Ia (GSD Ia) is a rare inherited disorder, with autosomal recessive determinism. It is characterized by hepatomegaly, short stature and hypoglycemia with lactic acidemia. The confirmation of diagnosis is based on the enzymatic assay performed on liver biopsy. For Tunisians patients, this biochemical test is performed abroad. The aim of our study is the molecular characterization of GSD Ia in Tunisian patients and the development of a molecular diagnosis tool. Our study included 27 patients from 23 unrelated families, mutation analysis revealed that the R83C mutation is the most frequent (65%, 30/46 mutant alleles), followed by the R170Q mutation (30%, 14/46 mutant alleles). The homogeneity of mutation spectrum of GSD Ia in Tunisia allows the development of a cost effective and reliable tool for the confirmation of clinical diagnosis among suspected GSD Ia patients.
Published: 2009

50. Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays

Author: Elodie Manié, Emmanuel Barillot, Marc-Henri Stern, Tatiana Popova, Dominique Stoppa-Lyonnet, Guillem Rigaill, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de Biologie des Tumeurs, INSTITUT CURIE, Mathématiques et Informatique Appliquées ( MIA-Paris ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Département de recherche translationnelle, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, This work is part of the 'Cancéropôle Ile-de-France-Région Ile-de-France-Hereditary Breast Cancer' program coordinated by DSL and MHS. This work also was supported by the INSERM, the Institut Curie, and its Translational Research Department. TP is supported by a grant from the Cancéropôle Ile-de-France-Région Ile-de-France. GR is supported by a grant from the Institut National du Cancer (INCa)., Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Mathématiques et Informatique Appliquées (MIA-Paris), AgroParisTech-Institut National de la Recherche Agronomique (INRA), MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Département de Recherche Translationnelle, Mines Paris - PSL (École nationale supérieure des mines de Paris), and BMC, Ed.
Subjects: Method, Loss of Heterozygosity, MESH : Models, Genetic, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, Allelic Imbalance, MESH : Breast Neoplasms, Genome, Loss of heterozygosity, MESH: Genotype, Automation, MESH: Ploidies, 0302 clinical medicine, Models, MESH: Automation, Genotype, MESH: Models, Genetic, MESH : Karyotyping, Genetics, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH: Genomics, Homozygote, MESH : Polymorphism, Single Nucleotide, Single Nucleotide, Genomics, MESH: Gene Expression Regulation, Neoplastic, SDV:GEN, Gene Expression Regulation, Neoplastic, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, MESH : Ploidies, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Homozygote, MESH : Gene Expression Regulation, Neoplastic, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH : Homozygote, Genetic, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], SNP, Humans, MESH: Genome, Polymorphism, MESH : Allelic Imbalance, 030304 developmental biology, MESH: Loss of Heterozygosity, Neoplastic, [SDV.GEN]Life Sciences [q-bio]/Genetics, Ploidies, MESH: Humans, Models, Genetic, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Genomics, MESH : Humans, MESH: Allelic Imbalance, Gene Expression Regulation, Karyotyping, SDV:BBM:GTP, Human genetics, MESH : Automation, Gene expression profiling, MESH: Karyotyping, MESH : Genome, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Breast Neoplasms, MESH : Loss of Heterozygosity
Abstract: GAP, a method for analyzing complex cancer genome profiles from SNP arrays, performs well even with poor quality data and rearranged genomes, We describe a method for automatic detection of absolute segmental copy numbers and genotype status in complex cancer genome profiles measured with single-nucleotide polymorphism (SNP) arrays. The method is based on pattern recognition of segmented and smoothed copy number and allelic imbalance profiles. Assignments were verified by DNA indexes of primary tumors and karyotypes of cell lines. The method performs well even for poor-quality data, low tumor content, and highly rearranged tumor genomes.
Published: 2009

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