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1. P828: GenIDA, an international participatory database to better characterize comorbidities of genetic forms of intellectual disability: Novel findings of DDX3X syndrome

Author: Pauline Burger, Valentin Ruault, David Genevieve, Elana Forbes, Lottie Morison, Angela Morgan, and Jean-Louis Mandel
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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2. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Author: Elsa Leitão, Christopher Schröder, Ilaria Parenti, Carine Dalle, Agnès Rastetter, Theresa Kühnel, Alma Kuechler, Sabine Kaya, Bénédicte Gérard, Elise Schaefer, Caroline Nava, Nathalie Drouot, Camille Engel, Juliette Piard, Bénédicte Duban-Bedu, Laurent Villard, Alexander P. A. Stegmann, Els K. Vanhoutte, Job A. J. Verdonschot, Frank J. Kaiser, Frédéric Tran Mau-Them, Marcello Scala, Pasquale Striano, Suzanna G. M. Frints, Emanuela Argilli, Elliott H. Sherr, Fikret Elder, Julien Buratti, Boris Keren, Cyril Mignot, Delphine Héron, Jean-Louis Mandel, Jozef Gecz, Vera M. Kalscheuer, Bernhard Horsthemke, Amélie Piton, and Christel Depienne
Subjects: Science
Abstract: Discovering disease genes on the X chromosome can be particularly challenging. Here, the authors use features of known disease genes and machine learning to predict genes that remain to be associated with disorders on this chromosome.
Published: 2022
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3. The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA

Author: Romain Coutelle, Morgane Boedec, Karlijn Vermeulen, Joost Kummeling, David A. Koolen, Tjitske Kleefstra, Camille Fournier, Florent Colin, Axelle Strehle, David Geneviève, Pauline Burger, and Jean-Louis Mandel
Subjects: Intellectual disability, Autism spectrum disorder, Behavioural problems, Genetic disorders, COVID-19, Self-report, Psychiatry, RC435-571
Abstract: Abstract Background Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. Methods To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients’ relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. Results In total 199 participants—144 children and 45 adults—with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. Conclusions Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.
Published: 2022
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4. AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model

Author: Karima Habbas, Oktay Cakil, Boglárka Zámbó, Ricardos Tabet, Fabrice Riet, Doulaye Dembele, Jean‐Louis Mandel, Michaël Hocquemiller, Ralph Laufer, Françoise Piguet, and Hervé Moine
Subjects: AAV, diacylglycerol kinase, Fmr1‐KO, FMRP, Fragile X syndrome, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.
Published: 2022
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5. O46: GenIDA, an international participatory database to better characterize comorbidities of genetic forms of intellectual disability: insights on Koolen-de Vries syndrome

Author: Pauline Burger, Florent Colin, Axelle Strehle, Timothée Mazzucotelli, Nicole Collot, Ariane Bouman, Daphna Landau Prat, David Geneviève, Valentin Ruault, Roseline Caumes, Thomas Smol, Jamal Ghoumid, Joost Kummeling, Charlotte Ockeloen, Tjitske Kleefstra, Pierre Parrend, Amélie Piton, David Koolen, and Jean-Louis Mandel
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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6. GenIDA, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with Koolen-de Vries syndrome

Author: Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel
Subjects: GenIDA, Intellectual disability, Koolen-de Vries syndrome, Neurodevelopmental disorders, Patient registry, Genetics, QH426-470, Medicine
Abstract: Purpose: GenIDA is an international patient registry for individuals diagnosed with intellectual disability, autism spectrum disorder, and/or epilepsy, which is based on an online questionnaire that is completed by parent caregivers. In this study, the GenIDA data on Koolen-de Vries syndrome (KdVS) was analyzed illustrating the value of GenIDA and patient/caregiver participation in rare genetic neurodevelopmental disorders (NDDs). Methods: Recruitment was done on the GenIDA website from November 2016 to February 2022. Clinical information on individuals with KdVS was extracted for in-depth analysis and for comparison with the GenIDA data of individuals diagnosed with other NDDs. Results: A total of 1417 patients/caregivers across 35 genetic conditions answered to the GenIDA questionnaire, including caregivers of 237 individuals with KdVS. GenIDA findings on KdVS were consistent with the existing literature, and there were no significant differences between individuals with a 17q21.31 microdeletion and those with a pathogenic variant in the KANSL1 gene. GenIDA provided detailed clinical information including features that are over-represented in KdVS compared with other NDDs (eg, laryngomalacia). Modeling of the natural history showed a positive development of speech and language over time and relatively good reading ability in KdVS. Valproate and oxcarbazepine were reported as effective antiepileptic drugs, and responses to open-ended questions indicated that childhood recurrent pneumonia and asthma are clinically relevant comorbidities that were not described in KdVS before. Conclusion: GenIDA is a powerful registry to collect and harness valuable data on rare NDDs. The study shows that caregiver-driven data collection is effective in terms of global recruitment and centralization of clinical data.
Published: 2023
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7. Heterogeneous Intracellular Localization and Expression of Ataxin-3

Author: Yvon Trottier, Géraldine Cancel, Isabelle An-Gourfinkel, Yves Lutz, Chantal Weber, Alexis Brice, Etienne Hirsch, and Jean-Louis Mandel
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Spinocerebellar ataxia type 3 or Machado–Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder caused by an unstable and expanded CAG trinucleotide repeat that leads to the expansion of a polyglutamine tract in a protein of unknown function, ataxin-3. We have generated and characterized a panel of monoclonal and polyclonal antibodies raised against ataxin-3 and used them to analyze its expression and localization. In Hela cells, multiple isoforms are expressed besides the major 55-kDa form. While the majority of ataxin-3 is cytosolic, both immunocytofluorescence and subcellular fractionation studies indicate the presence of ataxin-3, in particular, of some of the minor isoforms, in the nuclear and mitochodrial compartments. We also show that ataxin-3 can be phosphorylated. In the brain, only one ataxin-3 isoform containing the polyglutamine stretch was detected, and normal and mutated proteins were found equally expressed in all patient brain regions analyzed. In most neurons, ataxin-3 had a cytoplasmic, dendritic, and axonal localization. Some neurons presented an additional nuclear localization. Ataxin-3 is widely expressed throughout the brain, with a variable intensity specific for subpopulations of neurons. Its expression is, however, not restricted to regions that show intranuclear inclusions and neurodegeneration in SCA3/MJD.
Published: 1998
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8. 30 years of repeat expansion disorders : What have we learned and what are the remaining challenges?

Author: Jean-Louis Mandel, Christel Depienne, univOAK, Archive ouverte, 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Biomedical Research, Time Factors, Molecular Diagnostic Method, Medizin, Genes, Recessive, Review, Missed diagnosis, Biology, 03 medical and health sciences, 0302 clinical medicine, Tandem repeat, Genetics, Humans, Exome, Genetics (clinical), Genes, Dominant, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Anticipation, Genetic, Genome, Human, Founder Effect, Genetic architecture, 030104 developmental biology, Evolutionary biology, Identification (biology), Human genome, Trinucleotide Repeat Expansion, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.
Published: 2021

9. Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling

Author: Andréa Geoffroy, Julie Zumsteg, Hervé Moine, Boglarka Zambo, Laetitia Fouillen, Laetitia Schramm, Karima Habbas, Dimitri Heintz, Jean-Louis Mandel, Eric Flatter, Arnaud Duchon, Yann Herault, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], RNA-binding protein, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Loss function, 030304 developmental biology, Diacylglycerol kinase, 0303 health sciences, business.industry, Lipid signaling, medicine.disease, FMR1, 3. Good health, nervous system diseases, Fragile X syndrome, Endocrinology, lipids (amino acids, peptides, and proteins), business, Pioglitazone, 030217 neurology & neurosurgery, Homeostasis, medicine.drug
Abstract: Fragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling inFmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of theFmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.
Published: 2020

10. Spatial control of nucleoporin condensation by fragile X‐related proteins

Author: Inès Jmel Boyer, Stephane Schmucker, Katerina Jerabkova, Hervé Moine, Alessandro Berto, Laurent Guerard, Claudia Bagni, Jean-Louis Mandel, Laura Pacini, Charlotte Kleiss, Yannick Schwab, Paolo Ronchi, Sébastien Jacquemont, Arantxa Agote-Arán, Izabela Sumara, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and MOINE, Herve
Subjects: Protein family, [SDV]Life Sciences [q-bio], Dynein, FXR1, Biology, fmrp, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, nucleoporins, annulate lamellae, expression, phase separation Subject Category Membrane & Trafficking, medicine, Membrane & Intracellular Transport, Nuclear pore, fragile X syndrome, membrane, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, dynein, General Immunology and Microbiology, maturation, nuclear-pore complex, General Neuroscience, Settore BIO/13, diffusion, Articles, medicine.disease, phase-separation, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Fragile X syndrome, Cytoplasm, transport, Interphase, progression, Nucleoporin, phase separation, 030217 neurology & neurosurgery
Abstract: Nucleoporins (Nups) build highly organized nuclear pore complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve‐like hydrogel within the central channel of the NPCs. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknown. Here, we show that fragile X‐related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule‐dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule‐containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation., Fragile X‐related proteins and dynein inhibit ectopic phase separation of nucleoporins in the cytoplasm and facilitate their localization to the nuclear envelope during G1 phase of the cell cycle.
Published: 2020

11. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author: Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), 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 de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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 ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract: PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.
Published: 2020

12. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Author: Chris Balak, Hélène Dollfus, Sumaiya Iqbal, Newell Belnap, Kristin G. Monaghan, Lorida Llaci, Sampathkumar Rangasamy, Véronique Geoffroy, Jean-Louis Mandel, Dennis Lal, Jamel Chelly, Keri Ramsey, Maïté Courel, Kirsty McWalter, Ignazio S. Piras, Marcus Naymik, Rolph Pfundt, Michèle Ernoult-Lange, Wayne M. Jepsen, Vinodh Narayanan, Antony Le Béchec, Dominique Weil, Kristine K. Bachman, Ryan Richholt, Szabolcs Szelinger, Matthew J. Huentelman, Johanna ter Beest, Arthur Campbell, Ingrid M. Wentzensen, Francesca Mattioli, Marianne Bénard, Jean Muller, Jean-François Deleuze, Amélie Piton, Anne Boland, Elise Schaefer, Patrick Rump, Matt De Both, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], GeneDx [Gaithersburg, MD, USA], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Les Hôpitaux Universitaires de Strasbourg (HUS), Cologne Center for Genomics, University of Cologne, Laboratoire de Biologie du Développement [IBPS] (LBD), weil, dominique, The Translational Genomics Research Institute (TGen), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Groningen [Groningen], Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François JACOB (JACOB), 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), CEA- Saclay (CEA), Lerner Research Institute [Cleveland, OH, USA], Cleveland Clinic, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CDF (laboratoire)), Collège de France (CdF (institution)), and Bénard, Marianne
Subjects: [SDV]Life Sciences [q-bio], RecA domain, DENDRITES, DEAD-box RNA Helicases, 0302 clinical medicine, Missense mutation, NEURONS, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, DEAD-box, RNA Helicase A, [SDV] Life Sciences [q-bio], helicase, intellectual disability, missense variants, DDX3X, COMMON-CAUSE, mRNA metabolism, RNA helicase, processing bodies, DEAD box, PROTEINS, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, METABOLISM, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Proto-Oncogene Proteins, DDX6, TRANSLATIONAL REPRESSION, REVEALS, Humans, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, MUTATIONS, Helicase, RNA, DExD/H-box, FRAMEWORK, neurodevelopmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, p-bodies, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
Published: 2019

13. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author: Anne Boland, Alain Verloes, Jean-François Deleuze, Amélie Piton, Robert Olaso, Jean-Louis Mandel, Laura Mary, Laurence Faivre, Christine Coubes, Bénédicte Gérard, Elise Schaefer, David Geneviève, Claire Feger, Irina Giurgea, Estelle Colin, Francesca Mattioli, Salima El Chehadeh, Dana Timbolschi, Yline Capri, Jennifer Fabre-Teste, Elsa Nourisson, Elisabeth Flori, Magalie Barth, Laurence Perrin, Claire Redin, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Collège de France (CdF (institution)), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Biologie François JACOB (JACOB), 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), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique, Hôpital de Hautepierre [Strasbourg], 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), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de cytogénétique, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Génotypage, Institut de Génomique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Intellectual disability, Disease, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Transcription Factor 4, MESH: Young adult, MESH: Child, Hyperventilation, 10. No inequality, Child, MESH: Transcription factor 4 / genetics, Genetics (clinical), MESH: Hyperventilation / genetics, Sanger sequencing, Mutation, High-Throughput Nucleotide Sequencing, TCF4, 3. Good health, Phenotype, MESH: Facies, Child, Preschool, Cohort, symbols, Female, MESH: Hight-throughput Nucleotide sequencing, Adult, MESH: Mutation, Adolescent, MESH: Phenotype, Article, MESH: Child, preschool, 03 medical and health sciences, symbols.namesake, Young Adult, Genetics, medicine, Humans, MESH: Adolescent, MESH: Humans, MESH: Hyperventilation / diagnosis, business.industry, Facies, MESH: Adult, medicine.disease, MESH: Male, MESH: Intellectual Disability / pathology, Human genome, business, Large-Scale Sequencing, MESH: Female
Abstract: IF 3.636 (2017); International audience; High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Published: 2018

14. EuroPhenome: a repository for high-throughput mouse phenotyping data

Author: Karen B Avraham, Ramiro Ramirez-Solis, Michel Roux, Paul Potter, Vassilis Aidinis, Rudi Balling, Annemarie Zimprich, Andrew Blake, Pierre Dubus, FATIMA BOSCH, Ann-Marie Mallon, Paul Denny, Daniela Marazziti, CECILIA MANNIRONI, RAFAELE MATTEONI, Holger Maier, Jan Rozman, Marc Le Bert, Werner Muller, Martin Klingenspor, Daniela Vogt Weisenhorn, Elizabeth Cartwright, Nadia Rosenthal, Christine Podrini, David Richardson, Marcello Raspa, Lore Becker, Tura Ferre, John Hancock, Tim Beck, Markus W. Ollert, Natasha Karp, Eckhard Wolf, Sylvie Franckhauser, Ian Jackson, GIUSEPPEDOMENICO TOCCHINIVALENTINI, Liliane Michalik, Veronique Brault, Jean Louis Mandel, Martin Hrabe de Angelis, CHIARA DI PIETRO, ELENI DOUNI, Sabine Hölter-Koch, SOPHIA DJEBALI, Lydia Teboul, Amiel Dror, SABRINA PUTTI, JESUS RUBERTE, Wolfgang Wurst, Yann Herault, Lillian Garrett, Sukhpal Prehar, Jacqueline Marvel, Beatrice Desvergne, Silvia Mandillo, GIANCARLO DEIDDA, EUMODIC Consortium, [0000-0002-4362-7108], and Apollo - University of Cambridge Repository
Subjects: EMPRESS, Biochemistry & Molecular Biology, EUMODIC Consortium, Interface (computing), 05 Environmental Sciences, Data definition language, Functional annotation, Empress, Ontologies, Resource, Screens, Animals, Computational Biology/methods, Computational Biology/trends, Databases, Genetic, Information Storage and Retrieval/methods, Internet, Mice, Inbred C57BL, Inbred Strains, Knockout, Phe, Information Storage and Retrieval, Mice, Inbred Strains, Computational biology, Biology, Ontology (information science), computer.software_genre, Bioinformatics, 03 medical and health sciences, Annotation, 0302 clinical medicine, Databases, Genetic, Genetics, Databases, Protein, 030304 developmental biology, computer.programming_language, Mice, Knockout, 0303 health sciences, Science & Technology, Computational Biology, Biological Ontologies, Articles, 06 Biological Sciences, Pipeline (software), ONTOLOGIES, Protein Structure, Tertiary, Mice, Inbred C57BL, Phenotype, Programming Languages, 08 Information and Computing Sciences, Web service, Raw data, Life Sciences & Biomedicine, computer, FUNCTIONAL ANNOTATION, 030217 neurology & neurosurgery, Software, Developmental Biology
Abstract: The broad aim of biomedical science in the postgenomic era is to link genomic and phenotype information to allow deeper understanding of the processes leading from genomic changes to altered phenotype and disease. The EuroPhenome project (http://www.EuroPhenome.org) is a comprehensive resource for raw and annotated high-throughput phenotyping data arising from projects such as EUMODIC. EUMODIC is gathering data from the EMPReSSslim pipeline (http://www.empress.har.mrc.ac.uk/) which is performed on inbred mouse strains and knock-out lines arising from the EUCOMM project. The EuroPhenome interface allows the user to access the data via the phenotype or genotype. It also allows the user to access the data in a variety of ways, including graphical display, statistical analysis and access to the raw data via web services. The raw phenotyping data captured in EuroPhenome is annotated by an annotation pipeline which automatically identifies statistically different mutants from the appropriate baseline and assigns ontology terms for that specific test. Mutant phenotypes can be quickly identified using two EuroPhenome tools: PhenoMap, a graphical representation of statistically relevant phenotypes, and mining for a mutant using ontology terms. To assist with data definition and cross-database comparisons, phenotype data is annotated using combinations of terms from biological ontologies. © The Author(s) 2009. Published by Oxford University Press.
Published: 2017
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15. WD40-repeat 47 is essential for brain development via microtubule-mediated processes and autophagy

Author: Binnaz Yalcin, Meghna Kannan, Christel Wagner, Marna Roos, Bruno Rinaldi, Perrine Kretz, Lara Mcgillewie, Séverine Bär, Shilpi Minocha, Chrystelle Po, Jamel Chelly, Jean-Louis Mandel, Renato Borgatti, Amélie Piton, Stephan Collins, Craig Kinnear, Yann Herault, Sylvie Friant, Ben Loos, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Friant, Sylvie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Stellenbosch University, Université de Strasbourg (UNISTRA), Medical Research Council, Fédération de Médecine Translationelle de Strasbourg (FMTS), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Lausanne = University of Lausanne (UNIL), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: Erreur dates et n° de conférence dans l'url https://hal.archives-ouvertes.fr/hal-02378786.; International audience
Published: 2017

16. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Author: Patrick Callier, Angélique Quartier, Matthieu Jung, Brigitte Gilbert-Dussardier, Vincent des Portes, Claire Feger, Bernard Jost, Bénédicte Gérard, Stéphanie Le Gras, Daphné Lehalle, Elsa Nourisson, Anne-Sophie Casteleyn, Claire Redin, Julien Thevenon, Anne-Laure Mosca-Boidron, Laurence Faivre, Hélène Poquet, Frédéric Huet, Paul Kuentz, Christel Thauvin-Robinet, Véronique Geoffroy, Jean-Louis Mandel, Massimiliano Rossi, Gaetan Lesca, Alice Masurel, Patrick Edery, Benoit Trojak, Salima El Chehadeh, Stéphanie Maury, Jean Muller, Amélie Piton, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique (CHU de Dijon), Service de psychiatrie générale et addictologie [CHU de Dijon], French Ministry of Health Fondation Jerome Lejeune Agence de la Biomedecine, CREGEMES Agence Nationale de la Recherche MENESR et Fondation Recherche Medicale Regional Council of Burgundy, ANR-10-IDEX-0002,UNISTRA,UNISTRA(2010), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and ANR-10-IDEX-0002-02/10-IDEX-0002,UNISTRA,UNISTRA ( 2010 )
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, diagnosis, RNA Splicing, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Fragile X Mental Retardation Protein, 03 medical and health sciences, Exon, Genetic linkage, placebo-controlled trial, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Molecular genetics, Genetics, medicine, Humans, gene, Genetics (clinical), Mutation, intron 10, Siblings, Middle Aged, medicine.disease, FMR1, Human genetics, 3. Good health, Fragile X syndrome, developmental delay, of-the-literature, 030104 developmental biology, intellectual disability, Fragile X Syndrome, mental-retardation, Medical genetics, Female, point mutation, double-blind, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G > A (family 2) and a maternally inherited c.420-8A > G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
Published: 2017

17. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author: Amélie Piton, Melanie Bahlo, Paul J. Lockhart, Vesna Lukic, Caroline Nava, David J. Amor, Pierre Bitoun, Vicki Anderson, Fabien Lesne, Greta Gillies, Amanda G. Wood, Justine Guegan, Gail Robinson, Catherine Garel, Alexis Brice, Sarah E.M. Stephenson, Guy A. Rouleau, Aurélie Méneret, Delphine Héron, Kate Pope, Solveig Heide, Cyril Mignot, Emmanuel Roze, Angélique Quartier, Jean-Louis Mandel, Annalisa Paolino, Quentin Welniarz, Sylvie Odent, Florence Riant, George McGillivray, Linda J. Richards, Ilan Gobius, Elliott H. Sherr, Tania Attié-Bitach, Charles A. Galea, Timothy J. Edwards, Myriam Srour, Megan Spencer-Smith, Oriane Trouillard, Laura Morcom, Boris Keren, Christel Depienne, Marie Laure Moutard, Anne Faudet, Richard J. Leventer, Alissandra McIlroy, Agnès Rastetter, Thierry Billette de Villemeur, Simone Mandelstam, Jens Bunt, Martin B. Delatycki, Rick M. Tankard, Ashley P L Marsh, CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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], CHU Trousseau [APHP], Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Radiologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Montreal Neurological Hospital, McGill University Health Center [Montreal] (MUHC), CHU Necker - Enfants Malades [AP-HP], 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), Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Bioinformatics division, The Walter & Eliza Hall Institute of Medical Research, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-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), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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)-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), Collège de France (CdF (institution)), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -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 ), 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], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], 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 ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Neuroscience Paris Seine ( NPS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), McGill University Health Center [Montreal, Canada] ( MUHC ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], 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 ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Developmental Disabilities, Penetrance, Receptors, Cell Surface, Biology, Nervous System Malformations, Corpus callosum, medicine.disease_cause, Mirror movements, Article, Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Netrin, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Family, 10. No inequality, Agenesis of the corpus callosum, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tumor Suppressor Proteins, Brain, DCC Receptor, medicine.disease, Phenotype, 030104 developmental biology, nervous system, Female, Agenesis of Corpus Callosum, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract: International audience; Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.
Published: 2017

18. Fragile X syndrome

Author: Elizabeth Berry-Kravis, Jean-Louis Mandel, Paul J. Hagerman, Randi J Hagerman, Hervé Moine, Heather C. Hazlett, Nahum Sonenberg, R. Frank Kooy, Flora Tassone, Ilse Gantois, and Donald B. Bailey
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, business.industry, General Medicine, Impulsivity, Trinucleotide repeat disorder, medicine.disease, FMR1, Fragile X syndrome, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Fragile X Syndrome, 030225 pediatrics, Intellectual disability, Neuroplasticity, medicine, Humans, Autism, Human medicine, medicine.symptom, business, Psychiatry, Neuroscience, 030217 neurology & neurosurgery
Abstract: Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which > 200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.
Published: 2017

19. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Author: David J. Adams, Jamel Chelly, Lara Mcgillewie, Christel Wagner, Ben Loos, Bruno Rinaldi, Sylvie Friant, Stephan C. Collins, Craig J. Kinnear, Perrine F. Kretz, Renato Borgatti, Yann Herault, Jean-Louis Mandel, Juliette D. Godin, Efil Bayam, Binnaz Yalcin, Chrystelle Po, Meghna Kannan, Marna Roos, Shilpi Minocha, Séverine Bär, Peggy Tilly, Claire Chevalier, Amélie Piton, Friant, Sylvie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Lausanne = University of Lausanne (UNIL), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), 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), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Clinique de la Souris (ICS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), CNRS (S.F.), INSERM (E.B. and S.F.), Strasbourg University (S.F.), Initiatives d'Excellence (IDEX) 2015 Attractivite (S.B.), and Grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02 (to B.Y. and J.D.G.). C.K. is supported by funding from the South African Medical Research Council. B.Y. is supported by the Jerome Lejeune Foundation, the French National Research Agency (ANR-11-PDOC-0029), and the Gutenberg Circle., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Male, 0301 basic medicine, Microcephaly, autophagy, WD40 Repeats, Microtubule-associated protein, [SDV]Life Sciences [q-bio], Lissencephaly, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microtubules, Mice, 03 medical and health sciences, 0302 clinical medicine, WD40 repeat, Cell Movement, medicine, Animals, microcephaly, Growth cone, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Neurons, Multidisciplinary, Corpus Callosum Agenesis, Stem Cells, WD40-repeat proteins, Microfilament Proteins, Neurogenesis, Brain, medicine.disease, Neural stem cell, Mice, Inbred C57BL, corpus callosum agenesis, [SDV] Life Sciences [q-bio], neurogenesis, Phenotype, 030104 developmental biology, PNAS Plus, Female, Microtubule-Associated Proteins, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1 , Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
Published: 2017

20. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Author: Marjon van Slegtenhorst, Jean-Louis Mandel, Paul R. Mark, Jane Juusola, Gretchen Von Allmen, Elise Schaefer, Aurora Pujol, Grazia M.S. Mancini, Francesca Mattioli, Gaëlle Vieville, Marielle Alders, Mark Engelen, Charles Coutton, Klaus Dieterich, Alex Magee, Jan Maarten Cobben, Amélie Piton, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de génétique médicale d’Alsace, Belfast City Hospital, Spectrum Health [Grand Rapids], Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Grenoble Alpes - Site NORD [La Tronche], hôpital couple-enfant [CHU Grenoble Alpes], McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), 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)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut Albert Bonniot, GeneDx [Gaithersburg, MD, USA], Catalan Institution for Research & Advanced Studies [Barcelona, Catalonia, Spain] (ICREA), ARD - Amsterdam Reproduction and Development, Human Genetics, ANS - Cellular & Molecular Mechanisms, Paediatric Genetics, ACS - Pulmonary hypertension & thrombosis, and Clinical Genetics
Subjects: 0301 basic medicine, Adult, Male, Haploinsufficiency, Biology, Blepharophimosis, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, Report, Intellectual Disability, Genetics, medicine, Blepharoptosis, Humans, Child, Frameshift Mutation, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Genes, Dominant, Histone Acetyltransferases, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Point mutation, Nuclear Proteins, Acetylation, Methyltransferases, Syndrome, medicine.disease, Molecular biology, Hypotonia, DNA-Binding Proteins, 030104 developmental biology, Phenotype, Child, Preschool, Muscle Hypotonia, Female, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion
Abstract: Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs(∗)8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
Published: 2017

21. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author: Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge
Subjects: Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract: Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
Published: 2014

22. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome

Author: Delphine Minot, Sophie Chancenotte, Paul Kuentz, Yvan Henrenger, Mélanie Archimbaud-Devilliers, Christel Thauvin-Robinet, Audrey Creppy, Aurore Curie, Ezzat Ghosn, Alice Masurel-Paulet, Marie Ruffier-Bourdet, Daphné Lehalle, Julien Thevenon, Nicole Philip, Marlène Bonnet, Frédéric Huet, Claire Redin, Laurence Faivre, Jean-Louis Mandel, Amélie Piton, Gaëlle Blanchard, Odile Perret, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Référent des Troubles du Langage et des Apprentissages [CHU Dijon] (CRTLA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FHU TRANSLAD (CHU de Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de Neuropédiatrie, Hospices Civils de Lyon (HCL), Université de Technologie de Compiègne (UTC), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Chaire Génétique Humaine, Collège de France (CdF (institution)), Regional Council of Burgundy Fondation Jerome Lejeune Agence de Biomedecine, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Reference Troubles Langages & Apprentissages, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), FHU TRANSLAD, Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition ( L2C2 ), 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 ), Hospices Civils de Lyon ( HCL ), Université de Technologie de Compiègne [Compiègne] ( UTC ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), 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 ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génétique Humaine
Subjects: Male, 0301 basic medicine, Proband, Microcephaly, DNA Mutational Analysis, x-chromosome inactivation, SLC9A6, Gene mutation, exchanger, Epilepsy, Ocular Motility Disorders, 0302 clinical medicine, angelman-syndrome, X Chromosome Inactivation, Intellectual disability, microcephaly, Child, 10. No inequality, Genetics (clinical), Sequence Deletion, Genetics, Brain, Genetic Diseases, X-Linked, tool, Magnetic Resonance Imaging, Pedigree, 3. Good health, Phenotype, Female, Cerebellar atrophy, Christianson syndrome, medicine.symptom, Adult, Heterozygote, Sodium-Hydrogen Exchangers, Ataxia, Adolescent, learning disabilities linked mental-retardation, 03 medical and health sciences, cerebellar atrophy, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Angelman syndrome, medicine, Humans, Family, gene, Genetic Association Studies, business.industry, Facies, medicine.disease, 030104 developmental biology, splicing signals, Mutation, epilepsy, RNA Splice Sites, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.
Published: 2016

23. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases

Author: Martial Mallaret, Mathilde Renaud, Claire Redin, Nathalie Drouot, Jean Muller, Francois Severac, Jean Louis Mandel, Wahiba Hamza, Traki Benhassine, Lamia Ali-Pacha, Meriem Tazir, Alexandra Durr, Marie-Lorraine Monin, Cyril Mignot, Perrine Charles, Lionel Van Maldergem, Ludivine Chamard, Christel Thauvin-Robinet, Vincent Laugel, Lydie Burglen, Patrick Calvas, Marie-Céline Fleury, Christine Tranchant, Mathieu Anheim, Michel Koenig, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene [Alger] ( USTHB ), Service de Neurologie, CHU Mustapha, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Service de neurologie 1 [CHU Pitié-Salpétrière], Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Hôpital de Hautepierre [Strasbourg], Service de neuropédiatrie et pathologie du développement, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Génétique et d'Embryologie Médicale, Centre Hospitalier Universitaire de Toulouse, Ipsen Merz Actelion, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), CHU Trousseau [APHP], Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 [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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Male, 0301 basic medicine, Neurology, Bioinformatics, form, 0302 clinical medicine, Databases, Genetic, Recessive ataxia, Age of Onset, Neurogenetics, Neuroradiology, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, deficiency, cohort, Middle Aged, adck3, 3. Good health, Female, medicine.symptom, Algorithm, Algorithms, Adult, medicine.medical_specialty, Ataxia, Adolescent, Cerebellar Ataxia, Genes, Recessive, Physical examination, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, cabc1/adck3, Young Adult, 03 medical and health sciences, atrophy, Next generation sequencing, medicine, Humans, gene, Aged, Retrospective Studies, Cerebellar ataxia, business.industry, Electromyography, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Reproducibility of Results, mutations, 030104 developmental biology, phenotypic variability, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, ADCK3
Abstract: International audience; Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.
Published: 2016

24. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Author: Massimiliano Rossi, Boris Keren, François Feillet, Julien Tarabeux, Isabel Llano-Rivas, Florence Renaldo-Robin, Vincent Laugel, Patricia Bretones, Bérénice Doray, Marguerite Miguet, Géraldine Greff, Caroline Michot, Béatrice Digeon, Nadine Kempf, Nadège Calmels, Anne Cavau, Martine Doco-Fenzy, Claire Gasnier, Cathy Obringer, Jean-Louis Mandel, Pascal Sabouraud, Jesus Gardeazabal, Didier Bessis, Christel Depienne, Blanca Gener, Artur Mazur, Jean Muller, Sophie Julia, Geneviève Baujat, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'endocrinologie pédiatrique, Hôpital mère enfant, Bron, CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), BioCruces Research Institute, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Rzeszow University, Unité de Neurologie, Hôpital Robert Debré, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Eloi, University of the Basque Country [Bizkaia] (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de recherche en neurosciences de Lyon (CRNL), 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), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS)-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), Chaire Génétique Humaine, CHU Strasbourg - Hopital Civil, Laboratoire de Génétique Médicale, Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM) - Faculté de Médecine, Centre de référence maladies osseuses constitutionnelles CHU Necker, Hôpital Necker - Enfants malades, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), CHU Reims, CHU Félix Guyon, Université de Lorraine (UL) - Institut National de la Santé et de la Recherche Médicale (INSERM), University of the Basque Country [Bizkaia] (UPV/EHU) - Cruces University Hospital, Hôpital Purpan, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre de recherche en neurosciences de Lyon, Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Claude Bernard Lyon 1 (UCBL) - Université Jean Monnet - Saint-Etienne - PRES Université de Lyon, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP] - Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], 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), and HAL UPMC, Gestionnaire
Subjects: 0301 basic medicine, ERCC6, ERCC8, DNA Repair, DNA-Directed DNA Polymerase, Cockayne syndrome, Genetics(clinical), Pharmacology (medical), Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Medicine(all), Genetics, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, High-Throughput Nucleotide Sequencing, Nuclear Proteins, General Medicine, 3. Good health, DNA-Binding Proteins, Phenotype, POLH, NGS, Xeroderma pigmentosum, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, medicine, Humans, education, Xeroderma Pigmentosum Group D Protein, Research, DNA Helicases, xeroderma pigmentosum, medicine.disease, Endonucleases, 030104 developmental biology, DNA Repair Enzymes, Mutation, NER, ERCC2, ERCC3, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nucleotide excision repair, Transcription Factors, ERCC5
Abstract: Background Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS). Methods Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). Results We identified causative mutations in 17 out of the 40 patients (43 %). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. Conclusions Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0408-0) contains supplementary material, which is available to authorized users.
Published: 2016

25. Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients

Author: Clotilde Lagier-Tourenne, Catharina G. Faber, Benoit Arveiler, Cyril Goizet, Darren G. Monckton, Rhoda Stefanatos, Berit Adam, Hubert J.M. Smeets, Jean-Louis Mandel, Michel Koenig, Claudia Braida, Frank Spaans, Navdeep Mahajan, Christine E. M. de Die-Smulders, Florence Niel, Genetica & Celbiologie, Klinische Neurowetenschappen, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, and RS: GROW - School for Oncology and Reproduction
Subjects: musculoskeletal diseases, Male, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Locus (genetics), Biology, Myotonic dystrophy, Germline, law.invention, chemistry.chemical_compound, Trinucleotide Repeats, law, Genetics, medicine, Humans, Myotonic Dystrophy, Allele, Molecular Biology, Genetics (clinical), Polymerase chain reaction, Alleles, General Medicine, medicine.disease, Myotonia, Pedigree, chemistry, Mutation, Female, Trinucleotide Repeat Expansion, DNA
Abstract: Myotonic dystrophy type 1 (DM1) is one of the most variable inherited human disorders. It is characterized by the involvement of multiple tissues and is caused by the expansion of a highly unstable CTG repeat. Variation in disease severity is partially accounted for by the number of CTG repeats inherited. However, the basis of the variable tissue-specific symptoms is unknown. We have determined that an unusual Dutch family co-segregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks and early hearing loss, carries a complex variant repeat at the DM1 locus. The mutation comprises an expanded CTG tract at the 5'-end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3'-end. The complex variant repeat tract at the 3'-end of the array is relatively stable in both blood DNA and the maternal germ line, although the 5'-CTG tract remains genetically unstable and prone to expansion. Surprisingly though, even the pure 5'-CTG tract is more stable in blood DNA and the maternal germ line than archetypal DM1 alleles of a similar size. Complex variant repeats were also identified at the 3'-end of the CTG array of approximately 3-4% of unrelated DM1 patients. The observed polarity and the stabilizing effect of the variant repeats implicate a cis-acting modifier of mutational dynamics in the 3'-flanking DNA. The presence of such variant repeats very likely contributes toward the unusual symptoms in the Dutch family and additional symptomatic variation in DM1 via affects on both RNA toxicity and somatic instability.
Published: 2010

26. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

Author: Nathalie Drouot, Jaeho Lee, Fabrice A.C. Klein, Mustafa A. Salih, Matthis Synofzik, Martial Mallaret, Cyril Mignot, Peter Bauer, Mathilde Renaud, Christine Tranchant, Michel Koenig, Cari A. Sagum, Rebecca Schüle, Jean-Louis Mandel, Mathieu Anheim, Rajech Sharkia, Muhammad Mahajnah, Mark T. Bedford, C. Marcelo Aldaz, Ludger Schöls, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Département de Neurologie, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Chaire Génétique Humaine, Collège de France (CdF (institution)), Division of Pediatric Neurology, King Khalid University Hospital, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Male, epidemiology [Intellectual Disability], [SDV]Life Sciences [q-bio], Protein Structure, Secondary, Mice, 0302 clinical medicine, Missense mutation, Cells, Cultured, Genetics, Mice, Knockout, 0303 health sciences, genetics [Cerebellar Ataxia], tonic-clonic epilepsy, WWOX, Autosomal recessive cerebellar ataxia, Disease gene identification, 3. Good health, Pedigree, diagnosis [Cerebellar Ataxia], WW Domain-Containing Oxidoreductase, Female, epidemiology [Cerebellar Ataxia], medicine.symptom, Oxidoreductases, Adult, Ataxia, Mice, 129 Strain, Adolescent, Cerebellar Ataxia, Hereditary spastic paraplegia, genetics [Mutation, Missense], genetics [Epilepsy], Molecular Sequence Data, Mutation, Missense, Saudi Arabia, Biology, Polymorphism, Single Nucleotide, WW domain, 03 medical and health sciences, Young Adult, genetics [Tumor Suppressor Proteins], Intellectual Disability, medicine, Animals, Humans, ddc:610, Amino Acid Sequence, hereditary spastic paraplegia, 030304 developmental biology, genetics [Oxidoreductases], Epilepsy, epidemiology [Saudi Arabia], Cerebellar ataxia, Tumor Suppressor Proteins, ataxia, Original Articles, medicine.disease, diagnosis [Epilepsy], epidemiology [Epilepsy], WWOX protein, human, Mice, Inbred C57BL, diagnosis [Intellectual Disability], biology.protein, Neurology (clinical), genetics [Intellectual Disability], 030217 neurology & neurosurgery
Abstract: International audience; We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy.
Published: 2014

27. 20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

Author: Sophie Chancenotte, Jean Muller, Amélie Piton, Katell Peoc'h, Hélène Poquet, Stéphanie Le Gras, Jean-Marie Launay, Jean-Louis Mandel, Anne-Sophie Jaeger, Laurence Faivre, Bénédicte Gérard, Jean-Michel Pinoit, Yvan Herenger, Bernard Jost, Christel Thauvin-Robinet, Alice Masurel, Julien Thevenon, Frédéric Huet, Claire Redin, Marlène Bonnet, and Julia Lauer
Subjects: Male, Models, Molecular, Brunner syndrome, Nonsense mutation, Mutation, Missense, Article, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Monoamine Oxidase, Genetics (clinical), Family Health, biology, Base Sequence, Genetic heterogeneity, Point mutation, High-Throughput Nucleotide Sequencing, medicine.disease, Pedigree, Protein Structure, Tertiary, Autism spectrum disorder, Attention Deficit and Disruptive Behavior Disorders, Child Development Disorders, Pervasive, biology.protein, Autism, Female, Monoamine oxidase A
Abstract: Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene–environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.
Published: 2013

28. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alstrom Syndromes

Author: Jean Muller, Hélène Dollfus, Marie-Claire Vincent, Didier Lacombe, Pietro Chiurazzi, Oussema Mhamdi, Véronique Geoffroy, Jean-Louis Mandel, Marianne Till, Claire Redin, Bernard Jost, Florence Petit, Stéphanie Le Gras, Corinne Stoetzel, Ines Ouertani, Habiba Chaabouni, and Alain Verloes
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, BBS1, diagnosis, DNA Mutational Analysis, Cell Cycle Proteins, Biology, Settore MED/03 - GENETICA MEDICA, Joubert syndrome, Cohort Studies, Genetic Heterogeneity, Bardet–Biedl syndrome, Nephronophthisis, Molecular genetics, Genetics, medicine, Methods, Bardet-Biedl syndrome, Humans, Genetic Testing, Genetics (clinical), Alstrom Syndrome, Genetic Association Studies, Genetic testing, Sequence Deletion, multiplexing, medicine.diagnostic_test, Genetic heterogeneity, Genome, Human, Homozygote, Genetic Diseases, Inborn, High-Throughput Nucleotide Sequencing, Proteins, Reproducibility of Results, high-throughput sequencing, Exons, medicine.disease, Cytoskeletal Proteins, Targeted sequencing, ciliopathies, Alström syndrome
Abstract: Background Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alstrom syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes ( BBS1 - BBS16 ) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly. Method We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B . Results This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of ‘classical’ BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants. Conclusion This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.
Published: 2012

29. Identification of a two base pair deletion in five unrelated families with adrenoleukodystrophy: a possible hot spot for mutations

Author: Stephan Kemp, Marjolijn J. L. Ligtenberg, Peter G. Barth, Jean-Louis Mandel, B.M. van Geel, Claude-Olivier Sarde, R. Wolterman, B.A. van Oost, F. Schoute, Pieter A. Bolhuis, and Other departments
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, DNA, Complementary, endocrine system diseases, Base pair, Molecular Sequence Data, Biophysics, Hot spot (veterinary medicine), Biology, ATP Binding Cassette Transporter, Subfamily D, Member 1, Polymerase Chain Reaction, Biochemistry, Exon, Adenosine Triphosphate, Complementary DNA, Consensus Sequence, medicine, Humans, Point Mutation, In patient, Adrenoleukodystrophy, Molecular Biology, Gene, Genetics, Base Composition, Binding Sites, Base Sequence, Point mutation, Membrane Proteins, nutritional and metabolic diseases, Cell Biology, medicine.disease, Molecular biology, ATP-Binding Cassette Transporters, Female, Chromosome Deletion, Carrier Proteins
Abstract: The gene for X-linked adrenoleukodystrophy (ALD) was recently identified. Intragenic deletions of several kilobases were found in about 7% of patients. Point mutations, expected to be very heterogeneous, were identified so far in only two patients. We report the identification of a two base pair deletion at position 1801-1802 of the ALD cDNA, located within the fifth exon of the ALD gene, which precedes the two consensus motives for ATP-binding, This microdeletion was found in five out of 40 unrelated ALD kindreds, indicating that this position is a hot spot for mutations. The mutation was observed both in patients with childhood cerebral ALD (CCALD) and in patients with adrenomyeloneuropathy (AMN).
Published: 1994

30. Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease

Author: Serge Vicaire, Dominique Bonneau, Pierre Bitoun, Nicholas Katsanis, Sophie Hellé, Alice Goldenberg, Valérie Drouin-Garraud, Marie-Claire Vincent, Jean Marc Danse, Vincent Marion, Sabine Sigaudy, Joelle Roume, M. Hamdani, Sylvie Odent, Christine Francannet, Erica E. Davis, Alain Verloes, V. Bennouna-Greene, Jean Muller, Josseline Kaplan, Hélène Dollfus, Virginie Laurier, Jean-Louis Mandel, André Mégarbané, Carmen C. Leitch, Jane Green, Mireille Cossée, Corinne Stoetzel, Nicole Philip, Olivier Poch, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Laboratoire de diagnostic génétique, CHU Strasbourg, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (JHU), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), 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), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital 20 Août 1953, Service de Génétique et de Diagnostic Prénatal, Université de la Méditerranée - Aix-Marseille 2, Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Service de génétique médicale, CHI Poissy-Saint-Germain, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de génétique médicale [Hôpital de la Timone - APHM], 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), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, Department of Genetics, Memorial University of Newfoundland [St. John's], Center for Human Disease Modeling, Duke University [Durham], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Chaire Génétique Humaine, Collège de France (CdF (institution)), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Collège de France - Chaire Génétique Humaine, De Villemeur, Hervé, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Génétique Médicale, Université Louis Pasteur - Strasbourg I-Hôpital de Hautepierre [Strasbourg]-AVENIR-Inserm, Johns Hopkins University ( JHU ), Université Saint-Joseph de Beyrouth ( USJ ), 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 Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I ( UdA ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Jean Verdier, 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 de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Sud, Duke university [Durham], Université d'Angers ( UA ) -CHU Angers, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: BBS2, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, BBS1, Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Gene Duplication, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Gene duplication, Genetics, medicine, Missense mutation, Humans, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Genetic Testing, Bardet-Biedl Syndrome, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Chromatography, High Pressure Liquid, Polymorphism, Single-Stranded Conformational, 030304 developmental biology, Aged, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, 030305 genetics & heredity, Decision Trees, Homozygote, Chromosome Mapping, Sequence Analysis, DNA, Middle Aged, Disease gene identification, 3. Good health, Pedigree, BBS12, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, Microsatellite Repeats
Abstract: International audience; Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.
Published: 2010

31. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author: Peter Vollenweider, Leena Peltonen, Audrey Labalme, Jessica L. Buxton, Alessandra Ferrarini, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Marie Pigeyre, Sébastien Jacquemont, Vincent Mooser, Audrey Guilmatre, C. Lecoeur, Muriel Holder-Espinasse, Bettina Blaumeiser, Elena G. Bochukova, Ni Huang, Andrew Walley, Danielle Martinet, Peter Jacobson, B. Leheup, Marie-Pierre Lemaitre, A. Brioschi, Julia M. Keogh, Damien Sanlaville, Stephen O'Rahilly, Robert Sladek, Bruno Delobel, Fanny Stutzmann, Sophie Dupuis-Girod, Philippe Froguel, Muriel Gaillard, Anne Philippe, Katrin Männik, Jean-Marie Cuisset, M. Béri-Dexheimer, Lachlan J. M. Coin, Fei Chen, François Pattou, Katrin Õunap, Mari Nelis, A.-L. Hartikainen, Jean-Claude Chèvre, Philippe Jonveaux, Alice Goldenberg, Kay D. MacDermot, Elana Henning, Odile Boute, Sonia Bouquillon, Armand Valsesia, Valérie Malan, Stéphane Lobbens, R. F. Kooy, Alexandra I. F. Blakemore, Marie-Pierre Cordier, Lena M. S. Carlsson, Marjo-Riitta Järvelin, Lars Sjöström, Paul Elliott, C Le Caignec, Florence Fellmann, Nadège Calmels, Dominique Campion, M. M. van Haelst, Vincent Vatin, B. Balkau, Jacques S. Beckmann, Mark I. McCarthy, Robert Caiazzo, Jean-Louis Mandel, Joris Andrieux, Nouchine Hadjikhani, Catherine Vincent-Delorme, David Meyre, Ants Kurg, J. S. El-Sayed Moustafa, Johanna C. Andersson, Jean Chiesa, Michèle Mathieu-Dramard, R. Touraine, Tõnu Esko, Albert David, Alexandre Reymond, Priit Palta, Ghislaine Plessis, Andres Metspalu, Robin G. Walters, Vittorio Giusti, Richard J. Ellis, Bertrand Isidor, Anne-Emmanuelle Ambresin, A J de Smith, I. S. Farooqi, Matthew E. Hurles, Mario Falchi, Medical Research Council (MRC), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments
Subjects: Male, Aging, SAMPLE, Inheritance Patterns, Genome-wide association study, Penetrance, MC4R, Body Mass Index, Cohort Studies, 0302 clinical medicine, SH2B1, Missing heritability problem, Age of Onset, Child, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, Sex Characteristics, Multidisciplinary, Mental-Retardation, Adolescent Adult Age of Onset Aging Body Mass Index Case-Control Studies Child *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cognition Disorders/complications/genetics Cohort Studies Europe Female Genome-Wide Association Study Heterozygote Humans Inheritance Patterns/genetics Male Mutation/genetics Obesity/complications/*genetics/*physiopathology *Penetrance Reproducibility of Results Sex Characteristics Young Adult, 3. Good health, Multidisciplinary Sciences, Europe, Adolescent, Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Mutation/genetics, Obesity/complications, Obesity/genetics, Obesity/physiopathology, Reproducibility of Results, Young Adult, Medical genetics, Science & Technology - Other Topics, CHILDHOOD OBESITY, medicine.medical_specialty, Childhood Obesity, BIRTH, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, Article, Childhood obesity, 03 medical and health sciences, medicine, MICRODELETION, Obesity, GENOME-WIDE ASSOCIATION, AUTISM, education, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, MULTIDISCIPLINARY SCIENCES, FRAMESHIFT MUTATION, Individuals, medicine.disease, RISK LOCI, INDIVIDUALS, CIRCULAR BINARY SEGMENTATION, Mutation, Human medicine, Cognition Disorders, MENTAL-RETARDATION, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16
Abstract: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
Published: 2010

32. Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes

Author: Sophie Hellé, Israël Nisand, Vincent Marion, Sabine Sigaudy, Corinne Stoetzel, Marie-Claire Vincent, Laurence Faivre, Jean-Louis Mandel, Alain Verloes, Bérénice Doray, Jean-Marc Danse, Pierre Bitoun, Elise Schaefer, Christian P. Hamel, Alice Goldenberg, Hélène Dollfus, Dominique Bonneau, Sonia Finck, Myriam Durand, Muriel Holder, B. Viville, Mitochondrie : Régulations et Pathologie, and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Heart Defects, Congenital, BBS2, congenital, hereditary, and neonatal diseases and abnormalities, Genotype, Genetic counseling, [SDV]Life Sciences [q-bio], Hydrocolpos/diagnosis/genetics, Biology, Polydactyly/diagnosis/genetics, MKKS, McKusick–Kaufman syndrome, Diagnosis, Differential, 03 medical and health sciences, Genetic Heterogeneity, Bardet–Biedl syndrome, Diagnosis, Genetics, medicine, Humans, Abnormalities, Multiple, Bardet-Biedl Syndrome/diagnosis/genetics, Congenital/diagnosis/genetics, Bardet-Biedl Syndrome, Genetics (clinical), 030304 developmental biology, Heart Defects, Uterine Diseases, 0303 health sciences, Polydactyly, Molecular Diagnostic Techniques/methods, Genetic heterogeneity, 030305 genetics & heredity, fungi, Infant, Newborn, Infant, Hydrocolpos, General Medicine, Uterine Diseases/diagnosis/genetics, medicine.disease, Newborn, Phenotype, Molecular Diagnostic Techniques, Differential, Mutation, BBS12, Abnormalities, Multiple/diagnosis/genetics
Abstract: International audience; Hydrometrocolpos and polydactyly diagnosed in the prenatal period or early childhood may raise diagnostic dilemmas especially in distinguishing McKusick-Kaufman syndrome (MKKS) and the Bardet-Biedl syndrome (BBS). These two conditions can initially overlap. With time, the additional features of BBS appearing in childhood, such as retinitis pigmentosa, obesity, learning disabilities and progressive renal dysfunction allow clear differentiation between BBS and MKKS. Genotype overlap also exists, as mutations in the MKKS-BBS6 gene are found in both syndromes. We report 7 patients diagnosed in the neonatal period with hydrometrocolpos and polydactyly who carry mutations in various BBS genes (BBS6, BBS2, BBS10, BBS8 and BBS12), stressing the importance of wide BBS genotyping in patients with this clinical association for diagnosis, prognosis and genetic counselling.
Published: 2010

33. G.P.12.02 T-tubule disorganisation and defective excitation–contraction coupling in muscle fibres lacking myotubularin lipid phosphatase

Author: Nadia Messaddeq, Anna Buj-Bello, Céline Berbey, Christine Kretz, Vincent Jacquemond, Norbert Weiss, Despina Sanoudou, Jocelyn Laporte, Bruno Allard, Alan H. Beggs, L. Al-Qusairi, Jean-Louis Mandel, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon
Subjects: Myotubularin, Chemistry, Excitation–contraction coupling, Phosphatase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, T-tubule, medicine.anatomical_structure, Neurology, Biochemistry, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Genetics (clinical), ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2009

34. Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H

Author: Mireille Cossée, Clotilde Lagier-Tourenne, Claire Seguela, Michel Mohr, France Leturcq, Hulya Gundesli, Jamel Chelly, Christine Tranchant, Michel Koenig, Jean-Louis Mandel, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Département de Pathologie, Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medical Biology, Hacettepe University Faculty of Medicine, Département de Neurologie, CHU Strasbourg-Hopital Civil, Chaire Génétique Humaine, Collège de France (CdF (institution)), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, and Peney, Maité
Subjects: Genetic Markers, Male, Genotype, Ubiquitin-Protein Ligases, DNA Mutational Analysis, Mutation, Missense, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Frameshift mutation, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Testing, Muscular dystrophy, Muscle, Skeletal, Myopathy, Genetics (clinical), Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics, 0303 health sciences, Genetic heterogeneity, Homozygote, Middle Aged, medicine.disease, Arabs, Pedigree, Protein Structure, Tertiary, Muscular Dystrophies, Limb-Girdle, Neurology, Pediatrics, Perinatology and Child Health, Female, France, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Transcription Factors, SNP array, Limb-girdle muscular dystrophy
Abstract: International audience; Molecular diagnosis of monogenic diseases with high genetic heterogeneity is usually challenging. In the case of limb-girdle muscular dystrophy, multiplex Western blot analysis is a very useful initial step, but that often fails to identify the primarily affected protein. We report how homozygosity analysis using a genome-wide SNP array allowed us to solve the diagnostic enigma in a patient with a moderate form of LGMD, born from consanguineous parents. The genome-wide scan performed on the patient's DNA revealed several regions of homozygosity, that were compared to the location of known LGMD genes. One such region indeed contained the TRIM32 gene. This gene was previously found mutated in families with limb-girdle muscular dystrophy type 2H (LGMD2H), a mild autosomal recessive myopathy described in Hutterite populations and in 4 patients with a diagnosis of sarcotubular myopathy. A single missense mutation was found in all these patients, located in a conserved domain of the C-terminal part of the protein. Another missense mutation affecting the N-terminal part of TRIM32, observed in a single consanguineous Bedouin family, was reported to cause the phenotypically unrelated and genetically heterogeneous Bardet-Biedl syndrome, defining the BBS11 locus. Sequencing of TRIM32 in our patient revealed a distal frameshift mutation, c.1753_1766dup14 (p.Ile590Leu fsX38). Together with two recently reported mutations, this novel mutation confirms that integrity of the C-terminal domain of TRIM32 is necessary for muscle maintenance.
Published: 2009

35. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

Author: Vincent Marion, Jean Marc Danse, Dominique Schlicht, Michael Koch, Nadia Messaddeq, Hélène Dollfus, Elisabeth Flori, Jean-Louis Mandel, Corinne Stoetzel, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Laboratoire de Cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Chaire Génétique Humaine, Collège de France (CdF (institution)), Peney, Maité, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génétique Humaine
Subjects: MESH: Signal Transduction, MESH: Cell Differentiation, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Chaperonins, Chaperonins, BBS10, Group II Chaperonins, Biology, 03 medical and health sciences, 0302 clinical medicine, MESH: Bardet-Biedl Syndrome, GSK-3, MESH: Cilia, Internal medicine, Ciliogenesis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Adipocytes, Morphogenesis, MESH: Obesity, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cilia, Obesity, Bardet-Biedl Syndrome, MESH: Adipocytes, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Multidisciplinary, MESH: Humans, Adipogenesis, Cilium, Wnt signaling pathway, Cell Differentiation, Biological Sciences, medicine.disease, MESH: Morphogenesis, Cell biology, Ciliopathy, Endocrinology, Signal transduction, MESH: Adipogenesis, 030217 neurology & neurosurgery, MESH: Cells, Cultured, Signal Transduction
Abstract: International audience; Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally associated with severe obesity, but the underlying mechanism remains hypothetical and is generally proposed to be of neuroendocrine origin. In this study, we show that while the proliferating preadipocytes or mature adipocytes are nonciliated in culture, a typical primary cilium is present in differentiating preadipocytes. This transient cilium carries receptors for Wnt and Hedgehog pathways, linking this organelle to previously described regulatory pathways of adipogenesis. We also show that the BBS10 and BBS12 proteins are located within the basal body of this primary cilium and inhibition of their expression impairs ciliogenesis, activates the glycogen synthase kinase 3 pathway, and induces peroxisome proliferator-activated receptor nuclear accumulation, hence favoring adipogenesis. Moreover, adipocytes derived from BBS-patients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates to the pathogenesis of obesity in BBS.
Published: 2009

36. SPG11 spastic paraplegia : A new cause of juvenile parkinsonism

Author: Michel Koenig, Clotilde Lagier-Tourenne, Jean-Louis Mandel, Alexis Brice, Giovanni Stevanin, Christine Tranchant, Mathieu Anheim, Alexandra Durr, Paola S. Denora, Izzie Jacques Namer, Marie Fleury, Département de Neurologie, CHU Strasbourg-Hopital Civil, 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), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-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), Service de Biophysique et Médecine Nucléaire, CHU Strasbourg-Université Louis Pasteur - Strasbourg I-Hôpital de Hautepierre [Strasbourg], Collège de France - Chaire Génétique Humaine, Collège de France (CdF (institution)), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chaire Génétique Humaine, and Peney, Maité
Subjects: Adult, Male, medicine.medical_specialty, Pathology, Neurology, Adolescent, DNA Mutational Analysis, Neurological disorder, [SDV.GEN] Life Sciences [q-bio]/Genetics, Corpus callosum, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Parkinsonian Disorders, medicine, Spastic, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Resting tremor, 030304 developmental biology, Paraplegia, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Parkinsonism, Brain, Proteins, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Surgery, nervous system diseases, Peripheral neuropathy, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Psychology, 030217 neurology & neurosurgery
Abstract: International audience; Autosomal recessive hereditary spastic paraplegia (AR HSP) with thin corpus callosum (TCC) is a rare neurodegenerative disorder often caused by mutations in the gene encoding for spatacsin at the SPG11 locus on chromosome 15q. The disease is characterized by progressive spastic paraparesis and mental retardation which occur during the first two decades of life and frequently with peripheral neuropathy. Brain magnetic resonance imaging (MRI) reveals typical TCC with periventricular white matter changes. We describe two patients, of Turkish descent, from the same consanguineous family and affected with SPG11 in association with unusual early-onset parkinsonism. Parkinsonism occurred during the very early stages of SPG11 in both patients, being in one the inaugural symptom of the disease presented as a resting tremor with akinesia, rigidity and expressing an initial moderate levodopa-response that progressively weakened. The second patient presented a resting tremor with mild akinesia and no levodopa-response. Both patients were affected with progressive spastic paraparesis which had initially occurred at 15 and 12 years of age, respectively, in association with mild mental retardation and an axonal polyneuropathy. TCC with periventricular white matter changes (PWMC) was evident by MRI and (123)I-ioflupane SPECT was abnormal. Genetic analysis detected for both patients a new c.704_705delAT, p.H235RfsX12 homozygous mutation in SPG11. This report provides evidence that parkinsonism may initiate SPG11-linked HSP TCC and that SPG11 may cause juvenile parkinsonism.
Published: 2009

37. The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer

Author: Hervé Moine, Céline Schaeffer, Zhaoxia Tian, Jean-Louis Mandel, Murugan Subramanian, Marie-Cecile Didiot, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), Peney, Maité, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génétique Humaine
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Molecular Sequence Data, Exonic splicing enhancer, Regulatory Sequences, Ribonucleic Acid, Biology, PC12 Cells, Fragile X Mental Retardation Protein, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, Translational regulation, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Protein Isoforms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Cells, Cultured, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Messenger RNA, Binding Sites, Base Sequence, Adenine, Alternative splicing, Exons, FMR1, Molecular biology, Rats, nervous system diseases, G-Quadruplexes, Alternative Splicing, Protein Biosynthesis, RNA splicing, Mutagenesis, Site-Directed, RNA, 030217 neurology & neurosurgery, HeLa Cells, Minigene
Abstract: International audience; The fragile X mental retardation protein (FMRP) is a RNA-binding protein proposed to post-transcriptionally regulate the expression of genes important for neuronal development and synaptic plasticity. We previously demonstrated that FMRP binds to its own FMR1 mRNA via a guanine-quartet (G-quartet) RNA motif. However, the functional effect of this binding on FMR1 expression was not established. In this work, we characterized the FMRP binding site (FBS) within the FMR1 mRNA by a site directed mutagenesis approach and we investigated its importance for FMR1 expression. We show that the FBS in the FMR1 mRNA adopts two alternative G-quartet structures to which FMRP can equally bind. While FMRP binding to mRNAs is generally proposed to induce translational regulation, we found that mutations in the FMR1 mRNA suppressing binding to FMRP do not affect its translation in cellular models. We show instead that the FBS is a potent exonic splicing enhancer in a minigene system. Furthermore, FMR1 alternative splicing is affected by the intracellular level of FMRP. These data suggest that the G-quartet motif present in the FMR1 mRNA can act as a control element of its alternative splicing in a negative autoregulatory loop.
Published: 2008

38. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency

Author: Mirna Assoum, Olivier Poch, Christelle Thibault, Frédéric Plewniak, Samira Makri, Meriem Tazir, Cleverson Busso, David A. Lynch, Jean-Louis Mandel, Nathalie Drouot, Michio Hirano, Luis C. López, Salvatore DiMauro, M. Koenig, Catarina M. Quinzii, Mario H. Barros, Traki Benhassine, Clotilde Lagier-Tourenne, Christine Tranchant, Mathieu Anheim, Lamia Alipacha, Laurent Bianchetti, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Service de Neurologie, Hopital Mustapha, Etablissement Hospitalier Spécialisé Ali Ait Idir, Neurology Department, CHU Strasbourg, Département de Neurologie, CHU Strasbourg-Hopital Civil, Service de Neurologie [Strasbourg], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Sequence Analysis, DNA, Ubiquinone, Coenzymes, MESH: Phosphotransferases, MESH: Amino Acid Sequence, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Yeasts, COQ6, Missense mutation, Genetics(clinical), MESH: Ubiquinone, Genetics (clinical), Genetics, 0303 health sciences, Kinase, MESH: Yeasts, MESH: Coenzymes, Brain, Magnetic Resonance Imaging, Pedigree, MESH: Cerebellar Ataxia, Female, medicine.symptom, Coenzyme Q10 deficiency, Ataxia, MESH: Mutation, Cerebellar Ataxia, MESH: Pedigree, Molecular Sequence Data, Genes, Recessive, Biology, Article, 03 medical and health sciences, MESH: Brain, PDSS2, medicine, Humans, Amino Acid Sequence, MESH: Genes, Recessive, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Cerebellar ataxia, Phosphotransferases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, medicine.disease, MESH: Male, Mutation, MESH: Female, 030217 neurology & neurosurgery, ADCK3
Abstract: Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.
Published: 2008

39. C.P.1.10 Molecular mechanisms underlying X-linked myotubular myopathy

Author: Anna Buj-Bello, Christine Kretz, Jocelyn Laporte, Jean-Louis Mandel, Despina Sanoudou, L. Al-Qusairi, Alan H. Beggs, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon
Subjects: 0303 health sciences, Chemistry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, X-linked myotubular myopathy, Molecular biology, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2007

40. Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties: towards a length-dependent toxicity gradient

Author: Gabrielle Zeder-Lutz, Danièle Altschuh, Annalisa Pastore, Laura Masino, Yvon Trottier, Jean-Louis Mandel, Fabrice A.C. Klein, Mustapha Oulad-Abdelghani, Hélène Nierengarten, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Amino Acid Sequence, Biology, MESH: Neurodegenerative Diseases, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, MESH: Nuclear Magnetic Resonance, Biomolecular, Humans, Structural transition, MESH: Proteins, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Human proteins, 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Peptides, Aggregation kinetics, Proteins, Neurodegenerative Diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Toxicity, Biophysics, Peptides, 030217 neurology & neurosurgery, Heteronuclear single quantum coherence spectroscopy
Abstract: Abnormally expanded polyglutamine (polyQ) tracts provide a gain of toxic functions to nine otherwise unrelated human proteins and induce progressive neurodegenerative diseases. Over the past ten years, it was suggested that only polyQ tracts longer than a specific threshold adopt a particular structure, which would be the cause of the apparent polyQ length-dependent toxicity threshold observed in polyQ diseases. We have used a combination of biochemical and biophysical approaches to compare the structural properties of polyQ of pathogenic and non-pathogenic lengths under various conditions. We observe that pathogenic and non-pathogenic polyQ, as soluble species and upon interaction with a partner, during aggregation, or as mature aggregates, display very similar structural properties. PolyQ length only influences the aggregation kinetics and, to a lesser extent, the stability of the aggregates. We thus propose that polyQ toxicity does not depend on a structural transition occurring above a specific threshold, but rather that polyQ tracts are inherently toxic sequences, whose deleterious effect gradually increases with their length. We discuss how polyQ properties and other cellular factors may explain the existence of an apparent polyQ length-dependent toxicity threshold.
Published: 2007

41. Identification of a Novel BBS Gene (BBS12) Highlights the Major Role of a Vertebrate-Specific Branch of Chaperonin-Related Proteins in Bardet-Biedl Syndrome

Author: Dominique Bonneau, Olivier Poch, Jean Muller, Virginie Laurier, Evelyne Friederich, Frédéric Plewniak, Nicholas Katsanis, Carmen C. Leitch, Serge Vicaire, Norann A. Zaghloul, Hélène Dollfus, Jean-Louis Mandel, Jean-Marc Danse, Thomy de Ravel, Pierre Sarda, Christelle Thibault, Alain Verloes, Erica E. Davis, Richard A. Lewis, Corinne Stoetzel, Christian P. Hamel, Cécile Jacquelin, 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), Groupe de Recherche en Informatique et Mathématiques du Mirail (GRIMM), Université Toulouse - Jean Jaurès (UT2J), Laboratoire de Sciences de la Terre (LST), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Statistique et Probabilités (LSP), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Groupe de Recherche en Mathématiques et Informatique du Mirail (GRIMM), Neurobiologie de l'audition-plasticité synaptique, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Knowledge Technology Research Unit, Information Systems, University of Lancaster, Lancaster (KTRU), Lancaster University, Department of Mathematics [Sussex], University of Sussex, School of Biomedical Sciences, University of Queensland [Brisbane], Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Chaire Génétique Humaine, Collège de France (CdF (institution)), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Toulouse (UT)-Université de Toulouse (UT), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Collège de France - Chaire Génétique Humaine, Clinical sciences, Medical Genetics, Institute for European Studies, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: BBS2, Models, Molecular, Candidate gene, MESH: Chaperonins, Embryo, Nonmammalian, BBS1, Chaperonins, Group II Chaperonins, MKKS, 0302 clinical medicine, MESH: Bardet-Biedl Syndrome, Genetics(clinical), MESH: Animals, Chaperonins/genetics, 10. No inequality, Genetics (clinical), Zebrafish, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, Homozygote, Disease gene identification, Pedigree, BBS12, Chromosomes, Human, Pair 4, Bardet-Biedl Syndrome/genetics, MESH: Models, Molecular, MESH: Homozygote, MESH: Chromosomes, Human, Pair 4, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Protein family, MESH: Pedigree, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Bardet–Biedl syndrome, medicine, Animals, Humans, MESH: Zebrafish, Zebrafish/abnormalities, Bardet-Biedl Syndrome, 030304 developmental biology, MESH: Humans, MESH: Embryo, Nonmammalian, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chromosomes, Human, Pair 4/genetics, Embryo, Nonmammalian/abnormalities, medicine.disease, MESH: Oligonucleotide Array Sequence Analysis, Mutation, 030217 neurology & neurosurgery
Abstract: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.
Published: 2006

42. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy

Author: Christine Kretz, Nicolas Dondaine, Jean-Louis Mandel, Bernard Payrastre, Valérie Tosch, Jocelyn Laporte, Nancy Monroy, Edmar Zanoteli, Holger Maria Rohde, Hélène Tronchère, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Myotubularin, MESH: Catalytic Domain, Protein tyrosine phosphatase, MESH: Amino Acid Sequence, MESH: Variation (Genetics), MESH: Protein Structure, Tertiary, 0302 clinical medicine, Phosphatidylinositol Phosphates, Catalytic Domain, Chlorocebus aethiops, MESH: Animals, Genetics (clinical), Genetics, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Protein-Tyrosine-Phosphatase, MESH: Arginine, General Medicine, Protein Tyrosine Phosphatases, Non-Receptor, MESH: Phosphatidylinositol Phosphates, Pedigree, Cell biology, MESH: COS Cells, COS Cells, MESH: Phosphoric Monoester Hydrolases, Female, Chromosomes, Human, Pair 3, medicine.symptom, Myopathies, Structural, Congenital, MESH: Myopathies, Structural, Congenital, MESH: Pedigree, Molecular Sequence Data, Phosphatase, MESH: Chromosomes, Human, Pair 3, Mutation, Missense, MESH: Sequence Alignment, Biology, Arginine, Transfection, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Centronuclear myopathy, Muscle, Skeletal, Myopathy, Molecular Biology, 030304 developmental biology, Dynamin, MESH: Mutation, Missense, MESH: Humans, MESH: Molecular Sequence Data, MESH: Transfection, Genetic Variation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Congenital myopathy, MESH: Cercopithecus aethiops, Phosphoric Monoester Hydrolases, MESH: Male, Protein Structure, Tertiary, MESH: Cell Line, DNM2, Protein Tyrosine Phosphatases, Sequence Alignment, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.
Published: 2006

43. Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect

Author: Geoffrey Woods, Deepika Singh, Bernard Echenne, Sonja Finck, Manuela Antin, Mireille Cossée, Bénédicte Demeer, Jean-Louis Mandel, Vera M. Kalscheuer, Kelly Springell, Louis Vallee, Hélène Dollfus, Sridevi Hegde, B.K. Thelma, Patricia Blanchet, Olivier Hagens, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Proband, Microcephaly, Adolescent, Molecular Sequence Data, Biology, medicine.disease_cause, Short stature, Frameshift mutation, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Amino Acid Sequence, Family history, Child, Frameshift Mutation, Genetics (clinical), X chromosome, Sequence Deletion, 030304 developmental biology, 0303 health sciences, Mutation, Base Sequence, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Exons, medicine.disease, Pedigree, DNA-Binding Proteins, Child, Preschool, Female, medicine.symptom, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR). Clinical features frequently associated with MR were microcephaly and/or short stature. The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon. We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history. We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family. We also found two different 21 bp in-frame deletions (c.334-354del(21 bp) and c.393-413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat. Although such deletions have not been detected in 1180 X chromosomes from European controls, the c. 334-354del(21 bp) was subsequently found in two of 477 Xs from Indian controls. We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function. This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment.
Published: 2006

44. Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program

Author: Chantal Weber, Yvon Trottier, Aurélie Lardenois, Jean-Louis Mandel, Olivier Poch, Frédéric Chalmel, Gretta Abou-Sleymane, Karine Merienne, Dominique Helmlinger, Christelle Thibault, Didier Devys, Département de Pathologie Moléculaire, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Planétologie et d'Astrophysique de Grenoble (IPAG), Centre National d'Études Spatiales [Toulouse] (CNES)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Chaire Génétique Humaine, Collège de France (CdF (institution)), Institut de Planétologie et d'Astrophysique de Grenoble (IPAG ), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Collège de France - Chaire Génétique Humaine
Subjects: Retinal degeneration, Indoles, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Nerve Degeneration, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Developmental, MESH: Trinucleotide Repeat Expansion, MESH: Microscopy, Confocal, MESH: Animals, Fluorescent Antibody Technique, Indirect, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, MESH: Indoles, Neurons, Genetics, 0303 health sciences, MESH: Mice, Inbred CBA, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, MESH: Retina, Neurodegeneration, Gene Expression Regulation, Developmental, Cell Differentiation, MESH: Transcription Factors, General Medicine, MESH: Fluorescent Dyes, Phenotype, Cell biology, MESH: Reproducibility of Results, Spinocerebellar ataxia, Visual phototransduction, MESH: Cell Differentiation, MESH: Mice, Transgenic, Blotting, Western, Mice, Transgenic, Biology, Retina, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, MESH: Blotting, Western, MESH: Fluorescent Antibody Technique, Indirect, Animals, MESH: Mice, Molecular Biology, Transcription factor, Fluorescent Dyes, 030304 developmental biology, Gene Expression Profiling, Reproducibility of Results, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Mice, Inbred C57BL, Gene expression profiling, MESH: Oligonucleotide Array Sequence Analysis, Nerve Degeneration, Mice, Inbred CBA, Neuron differentiation, sense organs, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a group of inherited neurodegenerative diseases caused by polyglutamine (polyQ) expansion in corresponding proteins. Transcriptional alteration is a unifying feature of polyQ disorders; however, the relationship between polyQ-induced gene expression deregulation and degenerative processes remains unclear. R6/2 and R7E mouse models of HD and SCA7, respectively, present a comparable retinal degeneration characterized by progressive reduction of electroretinograph activity and important morphological changes of rod photoreceptors. The retina, which is a simple central nervous system tissue, allows correlating functional, morphological and molecular defects. Taking advantage of comparing polyQ-induced degeneration in two retina models, we combined gene expression profiling and molecular biology techniques to decipher the molecular pathways underlying polyQ expansion toxicity. We show that R7E and R6/2 retinal phenotype strongly correlates with loss of expression of a large cohort of genes specifically involved in phototransduction function and morphogenesis of differentiated rod photoreceptors. Accordingly, three key transcription factors (Nrl, Crx and Nr2e3) controlling rod differentiation genes, hence expression of photoreceptor specific traits, are down-regulated. Interestingly, other transcription factors known to cause inhibitory effects on photoreceptor differentiation when mis-expressed, such as Stat3, are aberrantly re-activated. Thus, our results suggest that independently from the protein context, polyQ expansion overrides the control of neuronal differentiation and maintenance, thereby causing dysfunction and degeneration.
Published: 2006

45. Deletion of both MTM1 and MTMR1 genes in a boy with myotubular myopathy

Author: Jean-Louis Mandel, Christine Kretz, Anna Buj-Bello, Alberto Alain Gabbai, Acary Souza Bulle Oliveira, José Claudio Casali da Rocha, Edmar Zanoteli, Jocelyn Laporte, Ana Beatriz Alvarez Perez, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Généthon, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetics, 0303 health sciences, MESH: Humans, MESH: Protein-Tyrosine-Phosphatase, MESH: Myopathies, Structural, Congenital, MESH: Child, Preschool, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Protein tyrosine phosphatase, Biology, Gene deletion, MESH: Male, 03 medical and health sciences, Exon, 0302 clinical medicine, MESH: Gene Deletion, MESH: Blotting, Southern, Myotubular Myopathy, MESH: Exons, Gene, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2005

46. Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

Author: Josef P. Kapfhammer, Vania Broccoli, Aurora Pujol, Jacqueline J.M Selhorst, Noëlle Callyzot, Ronald J.A. Wanders, Stephan Kemp, Isidre Ferrer, Petra A. W. Mooyer, Colette Hindelang, Peter Vreken, Nathalie Troffer-Charlier, Jean-Louis Mandel, Paediatric Metabolic Diseases, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Golgi Apparatus, ATP-binding cassette transporter, Endoplasmic Reticulum, MESH: Mice, Knockout, MESH: Spinal Cord, Mice, MESH: Spinocerebellar Degenerations, 0302 clinical medicine, Cerebellum, MESH: Behavior, Animal, MESH: Animals, Genetics (clinical), Spinocerebellar Degenerations, Genetics, Mice, Knockout, 0303 health sciences, education.field_of_study, Behavior, Animal, General Medicine, Peroxisome, Cell biology, Mitochondria, Spinal Cord, symbols, MESH: ATP-Binding Cassette Transporters, Adrenoleukodystrophy, medicine.symptom, Ataxia, MESH: Mitochondria, Population, Biology, ATP Binding Cassette Transporter, Subfamily D, 03 medical and health sciences, symbols.namesake, MESH: Golgi Apparatus, Sensory ataxia, MESH: Endoplasmic Reticulum, medicine, Animals, education, Molecular Biology, MESH: Mice, 030304 developmental biology, Endoplasmic reticulum, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Golgi apparatus, medicine.disease, MESH: Cerebellum, Disease Models, Animal, ATP-Binding Cassette Transporters, MESH: Disease Models, Animal, 030217 neurology & neurosurgery
Abstract: International audience; ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2-/- mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.
Published: 2005

47. Hsp70 and Hsp40 Chaperones Do Not Modulate Retinal Phenotype in SCA7 Mice

Author: Dominique Helmlinger, Jean-Louis Mandel, Didier Devys, Yvon Trottier, Jacques Bonnet, Centre de recherches de biochimie macromoléculaire (CRBM), Centre National de la Recherche Scientifique (CNRS)-IFR122-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Chaire Génétique Humaine, Collège de France (CdF (institution)), Département de Pathologie Moléculaire, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, and HELMLINGER, Dominique
Subjects: HD, Time Factors, [SDV]Life Sciences [q-bio], heat shock protein, electroretinogram, HA, Biochemistry, DAPI, Mice, 0302 clinical medicine, SBMA, Promoter Regions, Genetic, HSP (or Hsp), Heat-Shock Proteins, Neurons, 0303 health sciences, Microscopy, WT, Reverse Transcriptase Polymerase Chain Reaction, Huntington disease, reverse transcription, Immunohistochemistry, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Phenotype, ERG, Spinocerebellar ataxia, spinobulbar muscular atrophy, Plasmids, Genetically modified mouse, Proteasome Endopeptidase Complex, Rhodopsin, NI, Ataxin 7, DNA, Complementary, Transgene, Immunoblotting, Mice, Transgenic, Nerve Tissue Proteins, Biology, Transfection, Retina, RT, Cell Line, 03 medical and health sciences, Heat shock protein, medicine, Electroretinography, Animals, Humans, HSP70 Heat-Shock Proteins, hemagglutinin, Molecular Biology, 030304 developmental biology, Ataxin-7, Cell Nucleus, wild-type, Models, Genetic, Ubiquitin, Wild type, Cell Biology, HSP40 Heat-Shock Proteins, medicine.disease, Molecular biology, Hsp70, nuclear inclusion, Disease Models, Animal, spinocerebellar ataxia type 7, poly(Q), Chaperone (protein), Mutation, biology.protein, 6-dia- minido-2-phenylindole, Peptides, polyglutamine, 030217 neurology & neurosurgery, Molecular Chaperones
Abstract: International audience; Nine neurodegenerative diseases, including spinocer-ebellar ataxia type 7 (SCA7), are caused by the expansion of polyglutamine stretches in the respective disease causing proteins. A hallmark of these diseases is the aggregation of expanded polyglutamine-containing proteins in nuclear inclusions that also accumulate molecular chaperones and components of the ubiquitin-proteasome system. Manipulation of HSP70 and HSP40 chaperone levels has been shown to suppress aggregates in cellular models, prevent neuronal death in Drosoph-ila, and improve to some extent neurological symptoms in mouse models. An important issue in mammals is the relative expression levels of toxic and putative rescuing proteins. Furthermore, overexpression of both HSP70 and its co-factor HSP40/HDJ2 has never been investigated in mice. We decided to address this question in a SCA7 transgenic mouse model that progressively develops retinopathy, similar to SCA7 patients. To co-express HSP70 and HDJ2 with the polyglutamine protein, in the same cell type, at comparable levels and with the same time course, we generated transgenic mice that express the heat shock proteins specifically in rod photorecep-tors. While co-expression of HSP70 with its co-factor HDJ2 efficiently suppressed mutant ataxin-7 aggrega-tion in transfected cells, they did not prevent either neuronal toxicity or aggregate formation in SCA7 mice. Furthermore, nuclear inclusions in SCA7 mice were composed of a cleaved mutant ataxin-7 fragment, whereas they contained the full-length protein in trans-fected cells. We propose that differences in the aggrega-tion process might account for the different effects of chaperone overexpression in cellular and animal models of polyglutamine diseases. Spinocerebellar ataxia type 7 (SCA7) 1 is a dominantly inherited neurodegenerative disorder, characterized by late-onset neuronal loss in cerebellum, brainstem, and retina (1). SCA7 is caused by an abnormal expansion of a polyglutamine (poly(Q)) tract (38-460 repeats) in the SCA7 gene product ataxin-7 (2), a 892-amino acid protein recently identified as a new component of a multisubunit transcriptional complex (3). Eight other neurodegenerative diseases are caused by a CAG/poly(Q) repeat expansion, including Huntington disease (HD), denta-torubro-pallidoluysian atrophy, spinobulbar muscular atrophy (SBMA) and spinocerebellar ataxia types 1, 2, 3, 6, and 17. Genetic and molecular studies indicate that poly(Q) tracts confer a novel toxic function to the otherwise unrelated proteins, but the mechanisms by which poly(Q) expansions lead to neu-rodegeneration remain unclear (4, 5). All of these diseases are characterized by continuous accumulation of mutant proteins in insoluble aggregates, typically forming nuclear inclusions (NIs) (6). NIs have been shown to stain positively for ubiquitin, chaperones (mainly heat shock proteins), and proteasome subunits, in various cellular and animal models of poly(Q) diseases, as well as in post-mortem patient brains (7, 8). Several SCA7 mouse models, which reproduce many features of the human situation, display numerous NIs consistently stained for ubiquitin, proteasome sub-units, and chaperones (HSP70, HSC70, and HDJ2) (9-12). In SCA7 patient brains, HDJ2, ubiquitin, and 19 S proteasome subunits co-localize with NIs (13-15). Furthermore, the levels of several chaperones, including the HSP70 and the HSP40 chaperones HDJ1 and HDJ2, were shown to be reduced in SCA7 and/or HD mouse models (16, 17). Altogether, these findings suggested that protein misfolding and impaired clearance might be a common pathogenic event in poly(Q) diseases. Accordingly, several studies showed that overexpression of chaperones in cells reduces aggregate formation and, in some cases, suppresses poly(Q) toxicity (reviewed in Refs. 8 and 18). Genetic screens, in Drosophila models overexpressing mutant ataxin-1 or a pure 127Q stretch, identified molecular chaperones and components of the ubiquitin-proteasome pathway as strong modulators of poly(Q)-induced toxicity (19, 20). In particular , deletion of HSP70 genes exacerbated SCA1 or SBMA fly phenotypes, whereas overexpression of HSP70 or HDJ1 suppressed neurodegeneration in various Drosophila models (19-24). Furthermore, Chan et al. (25) showed that HSP70 and HDJ1 synergistically suppressed poly(Q) toxicity in a SCA3 fly model. These chaperones work together in an ATP-dependent manner, notably to help refold denaturated and aggregated proteins. HSP40 co-chaperones recognize abnormally folded polypeptide substrates, present them to HSP70, and stimulate HSP70 ATPase activity (26).
Published: 2004

48. Disease Progression Despite Early Loss of Polyglutamine Protein Expression in SCA7 Mouse Model

Author: Gretta Abou-Sleymane, Didier Devys, Yvon Trottier, Chantal Weber, Jean-Louis Mandel, Dominique Helmlinger, Gaël Yvert, Stephane Rousseau, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), 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: Retinal degeneration, retina, [SDV]Life Sciences [q-bio], Mice, 0302 clinical medicine, Gene expression, Transgenes, Promoter Regions, Genetic, 0303 health sciences, Huntingtin Protein, biology, General Neuroscience, Retinal Degeneration, Age Factors, neurodegeneration, Gene Expression Regulation, Developmental, Nuclear Proteins, Recombinant Proteins, Cell biology, Huntington Disease, Spinocerebellar ataxia, Disease Progression, Photoreceptor Cells, Vertebrate, Genetically modified mouse, Rhodopsin, Ataxin 7, Macromolecular Substances, Transgene, Photoreceptor activity, Down-Regulation, Mice, Transgenic, Nerve Tissue Proteins, 03 medical and health sciences, Downregulation and upregulation, reversibility, Neurobiology of Disease, medicine, Electroretinography, Animals, Spinocerebellar Ataxias, transcriptional alteration, 030304 developmental biology, Ataxin-7, medicine.disease, Molecular biology, Disease Models, Animal, biology.protein, aggregates, Peptides, Trinucleotide Repeat Expansion, polyglutamine, 030217 neurology & neurosurgery
Abstract: Nine neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) are caused by an expansion of a polyglutamine (polyQ) stretch in the respective proteins. Aggregation of expanded polyQ-containing proteins into the nucleus is a hallmark of these diseases. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of these diseases. Using SCA7 and HD mouse models in which we recently described a retinal phenotype, we investigated whether altered gene expression underlies photoreceptor dysfunction. In both models, rhodopsin promoter activity was early and dramatically repressed, suggesting that downregulation of photoreceptor-specific genes plays a major role in polyQ-induced retinal dysfunction. Because the rhodopsin promoter drives mutant ataxin-7 expression in our SCA7 mice, we also assessed whether downregulation of mutantSCA7transgene would reverse retinopathy progression and aggregate formation. Although residual expression of mutant ataxin-7 was found negligible from 9 weeks of age, SCA7 transgenic mice showed a progressive decline of photoreceptor activity leading to a complete loss of electroretinographic responses from 1 year of age. At this age, aggregates were cleared in only half of the photoreceptors, indicating that their formation is not fully reversible in this model. We demonstrate here that abolishing full-length mutant ataxin-7 expression did not reverse retinopathy progression in SCA7 mice, raising the possibility that some polyQ-induced pathological events might be irreversible.
Published: 2004

49. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype

Author: Wolfram Kress, Anna Buj-Bello, Clotilde Lagier-Tourenne, Sabina Gallati, Norma B. Romero, Frank Baas, Giuseppe Novelli, Olivier Caron, Maria Rosaria D'Apice, Jean-Louis Mandel, Valérie Biancalana, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Genome Analysis
Subjects: Adult, Male, Adolescent, Myotubularin, Biology, medicine.disease_cause, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Missense mutation, Centronuclear myopathy, Child, Muscle, Skeletal, Polymorphism, Single-Stranded Conformational, Genetics (clinical), X chromosome, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, 030304 developmental biology, Chromosomes, Human, X, 0303 health sciences, Mutation, Infant, Newborn, Genetic Variation, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, Exons, Protein Tyrosine Phosphatases, Non-Receptor, medicine.disease, Phenotype, X-linked myotubular myopathy, Pedigree, 3. Good health, Neonatal hypotonia, Child, Preschool, Female, Protein Tyrosine Phosphatases, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: X-linked myotubular myopathy is characterised by neonatal hypotonia, muscle weakness and respiratory distress in affected males, leading often to early death, although prolonged survival is observed in milder forms, or as a result of prolongation of ventilation support. It is caused by mutations in the MTM1 gene, which encodes a phosphatase called myotubularin, which has been highly conserved during evolution, down to yeasts ( S. cerevisiae and S. pombe). To date, 251 mutations have been identified in unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene. We have found additional mutations in 77 patients, including 35 novel ones. We identified a missense mutation N180K in a 67-year-old grandfather (the oldest known patient with an MTM1 mutation), previously suspected to have autosomal centronuclear myopathy, and in his two grandsons also mildly affected. Mild and moderate phenotypes associated with novel missense mutations and with a translation initiation defect mutation are discussed, as well as severe phenotypes associated with particular novel mutations. With the present report, 192 different mutations in the MTM1 gene have been described in 328 families. The spectrum of mutations is now enlarged from the very severe classic neonatal phenotype to very mild phenotype allowing survival to the age of 67 years.
Published: 2003

50. The N-terminus of the fragile X mental retardation protein contains a novel domain involved in dimerization and RNA binding

Author: Stephen R. Martin, F. Dal Piaz, Jean-Louis Mandel, Annalisa Pastore, Piero Pucci, Barbara Bardoni, Salvatore Adinolfi, Andres Ramos, Adinolfi, S., Ramos, A., Martin, S. R., Dal Piaz, F., Pucci, P., Bardoni, B., Mandel, J. L., Pastore, A, Adinolfi, S, Ramos, A, Martin, Sr, DAL PIAZ, F, Pucci, Pietro, Bardoni, B, Mandel, Jl, and Pastore, A.
Subjects: Protein Folding, family, Molecular Sequence Data, MRNP, translation, Sequence alignment, RNA-binding protein, Nerve Tissue Proteins, Biology, Biochemistry, Protein Structure, Secondary, Messenger-RNA, FMR-1 expression, identification, MRNP, association, translation, interacts, granules, mutation, family, FMR-1 expression, Fragile X Mental Retardation Protein, Protein structure, Messenger-RNA, medicine, Humans, Amino Acid Sequence, Peptide sequence, Psychological repression, Genetics, association, RNA, RNA-Binding Proteins, medicine.disease, Protein Structure, Tertiary, Fragile X syndrome, interacts, Fragile X Syndrome, identification, Protein folding, mutation, Dimerization, Sequence Alignment, granules
Abstract: Fragile X syndrome, the most common cause of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein (FMRP). The emerging picture is that FMRP is involved in repression of translation through a complex network of protein-protein and protein-RNA interactions. Very little structural information is, however, available for FMRP that could help to understand its function. In particular, no structural studies are available about the N-terminus of the protein, a highly conserved region which is involved in several molecular interactions. Here, we explore systematically the ability of the FMRP N-terminus to form independently folded units (domains). We produced deletion mutants and tested their fold and functional properties by mutually complementary biophysical and biochemical techniques. On the basis of our data, we conclude that the N-terminus contains a domain, that we named NDF, comprising the first 134 amino acids. Most interestingly, NDF comprises two copies of a newly identified Agenet motif. NDF is thermally stable and has a high content of beta structure. In addition to being able to bind to RNA and to recognize some of the FMRP interacting proteins, NDF forms stable dimers and is able to interact, although weakly, with the full-length protein. Our data provide conclusive evidence that NDF is a novel motif for protein-protein and protein-RNA interactions and contains a previously unidentified dimerization site.
Published: 2003

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