Author: "Patrick, Nitschke" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. Diagnosis of Menke‐Hennekam syndrome by prenatal whole exome sequencing and review of prenatal signs

Author: Guillaume Cogan, Nicolas Bourgon, Roxana Borghese, Emmanuel Julien, Aurélia Jaquette, Bertrand Stos, Amale Achaiaa, Sophie Chuon, Patrick Nitschke, Cécile Fourrage, Julien Stirnemann, Lucile Boutaud, and Tania Attie‐Bitach
Subjects: fetal anomalies, Menke‐Hennekam syndrome, molecular genetics, CREBBP, Genetics, QH426-470
Abstract: Abstract Introduction CREBBP truncating mutations and deletions are responsible for the well‐known Rubinstein‐Taybi syndrome. Recently, a new, distinct CREBBP‐linked syndrome has been described: missense mutations located at the 3′ end of exon 30 and the 5′ portion of exon 31 induce Menke‐Hennekam syndrome. Patients with this syndrome present a recognizable facial dysmorphism, intellectual disability of variable severity, microcephaly, short stature, autism, epilepsy, visual and hearing impairments, feeding problems, upper airway infections, scoliosis, and/or kyphosis. To date, all diagnoses were made postnatally. Method and Case Report Trio‐whole exome sequencing (WES) was performed in a fetus showing increased nuchal translucency persistence and aorta abnormalities at 28 weeks of gestation (WG). Results WES revealed a CREBBP de novo missense mutation (c.5602C>T; p.Arg1868Trp) in exon 31, previously reported as the cause of Menke‐Hennekam syndrome. Termination of pregnancy was performed at 32 WG. We further reviewed the prenatal signs of Menke‐Hennekam syndrome already reported. Among the 35 patients reported and diagnosed postnatally up to this day, 15 presented recognizable prenatal signs, the most frequent being intra‐uterine growth retardation, brain, and cardiovascular anomalies. Conclusion Menke‐Hennekam is a rare syndrome with unspecific, heterogeneous, and inconstant prenatal symptoms occurring most frequently with the c.5602C>T, p.(Arg1868Trp) mutation. Therefore, the prenatal diagnosis of Menke‐Hennekam syndrome is only possible by molecular investigation. Moreover, this case report and review reinforce the importance of performing prenatal WES when unspecific signs are present on imaging.
Published: 2023
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2. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Author: Athanasia Stoupa, Frédéric Adam, Dulanjalee Kariyawasam, Catherine Strassel, Sanjay Gawade, Gabor Szinnai, Alexandre Kauskot, Dominique Lasne, Carsten Janke, Kathiresan Natarajan, Alain Schmitt, Christine Bole‐Feysot, Patrick Nitschke, Juliane Léger, Fabienne Jabot‐Hanin, Frédéric Tores, Anita Michel, Arnold Munnich, Claude Besmond, Raphaël Scharfmann, François Lanza, Delphine Borgel, Michel Polak, and Aurore Carré
Subjects: congenital hypothyroidism, macroplatelets, mutations, thyroid dysgenesis, TUBB1, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
Published: 2018
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3. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1007386.].
Published: 2018
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4. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
Published: 2018
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5. Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling

Author: Lynn Pais, Anna Pelet, Wilhelmina S. Kerstjens-Frederikse, Christine Bole-Feysot, Yunia Sribudiani, Stanislas Lyonnet, Natasha Shur, Valérie Cormier-Daire, Louise Galmiche, Cécile Masson, Christopher T. Gordon, Chelsea Kois, Céline Huber, John A. Pugh, Simon Sadedin, Thuy-Linh Le, Nicolas Goudin, Tania Attié-Bitach, Susan M. White, Tiong Yang Tan, Geneviève Baujat, Valérie Serre, Xiaomin Dong, Mohammed Zarhrate, Patrick Nitschke, Jeanne Amiel, John Christodoulou, Frans W. Verheijen, Sophie Thomas, R Hofstra, Salima El Chehadeh, Valerie Mayne, Université Paris Cité (UPC), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Embryology and genetics of human malformation (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies (Equipe Inserm U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Genetics and Development of the Cerebral Cortex (Equipe Inserm U1163), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Clinical Genetics
Subjects: 0301 basic medicine, Male, Models, Molecular, Developmental Disabilities, [SDV]Life Sciences [q-bio], HIRSCHSPRUNG DISEASE, INTRAFLAGELLAR TRANSPORT PROTEIN, ACTIVATION, 0302 clinical medicine, Neoplasms, Sonic hedgehog, Child, Genetics (clinical), Nuclear Proteins, PRIMARY CILIUM, Smoothened Receptor, Hedgehog signaling pathway, Cell biology, Pedigree, Child, Preschool, Female, Signal Transduction, Patched, Nerve Tissue Proteins, Biology, Zinc Finger Protein Gli2, Article, 03 medical and health sciences, HYPOTHALAMIC HAMARTOMA, Zinc Finger Protein Gli3, GLI2, Ciliogenesis, NERVOUS-SYSTEM DEVELOPMENT, Genetics, Humans, Hedgehog Proteins, Cilia, Hedgehog, Alleles, Base Sequence, SONIC HEDGEHOG, MUTATIONS, Infant, CILIARY, 030104 developmental biology, biology.protein, Smoothened, 030217 neurology & neurosurgery, GLI
Abstract: The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report biallelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
Published: 2020

6. Somatic genetic rescue of a germline ribosome assembly defect

Author: Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]
Subjects: Somatic cell, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Germline, 631/208/737, 692/699/1541, Ribosome assembly, 13/1, 0302 clinical medicine, hemic and lymphatic diseases, 38/22, Dictyostelium, Eukaryotic Initiation Factors, Child, Cells, Cultured, Biological Phenomena, Genetics, 0303 health sciences, Multidisciplinary, 631/208/514/2254, article, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Ribosome Subunits, Large, Eukaryotic, Ribosome, Shwachman-Diamond Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], 64/24, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, Drosophila, Haematological diseases, Protein Binding, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Science, 45/23, Saccharomyces cerevisiae, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Young Adult, Germline mutation, Animals, Humans, Gene, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Sequence Homology, Amino Acid, Eukaryotic Large Ribosomal Subunit, Point mutation, Infant, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, SBDS, 96/44, Peptide Elongation Factors, Germ Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, Mutation, Next-generation sequencing, 631/337/574/1789, Ribosomes
Abstract: Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
Published: 2021

7. Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Author: Cécile Jeanpierre, Vincent Jung, Aurore Pouliet, Katta M. Girisha, Alexandre Benmerah, Camille Humbert, Charlotte Mechler, Sophie Saunier, Ida Chiara Guerrera, Patrick Nitschke, Kathryn Millar, Quentin Siour, Meriem Garfa-Traore, Anju Shukla, Céline Huber, Marion Delous, Esben Lorentzen, David Chitayat, Marie Alice Dupont, Anni Christensen, Marie Injeyan, Valérie Cormier-Daire, and Patrick Shannon
Subjects: Male, Centriole, DNA Mutational Analysis, Microtubules, Ciliopathies, Animals, Genetically Modified, Consanguinity, 0302 clinical medicine, Missense mutation, Child, Zebrafish, Genetics (clinical), 0303 health sciences, Cilium, Homozygote, Intracellular Signaling Peptides and Proteins, General Medicine, Pedigree, Cell biology, Sensenbrenner syndrome, Phenotype, Child, Preschool, Female, Protein Binding, Genotype, Biology, 03 medical and health sciences, Intraflagellar transport, Trimethoprim, Sulfamethoxazole Drug Combination, Exome Sequencing, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cilia, Molecular Biology, Genetic Association Studies, 030304 developmental biology, Centrosome, Infant, medicine.disease, Ciliopathy, Mutation, sense organs, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.
Published: 2019

8. 16p13.11p11.2 triplication syndrome: a new recognizable genomic disorder characterized by optical genome mapping and whole genome sequencing

Author: Romain Nicolle, Karine Siquier-Pernet, Marlène Rio, Anne Guimier, Emmanuelle Ollivier, Patrick Nitschke, Christine Bole-Feysot, Serge Romana, Alex Hastie, Vincent Cantagrel, and Valérie Malan
Subjects: Chromosome Aberrations, Segmental Duplications, Genomic, Whole Genome Sequencing, Genetics, Chromosome Mapping, Humans, Genomics, Syndrome, Genetics (clinical), Article
Abstract: Highly identical segmental duplications (SDs) account for over 5% of the human genome and are enriched in the short arm of the chromosome 16. These SDs are susceptibility factors for recurrent chromosomal rearrangements mediated by non-allelic homologous recombination (NAHR). Chromosomal microarray analysis (CMA) has been widely used as the first-tier test for individuals with developmental disabilities and/or congenital anomalies and several genomic disorders involving the 16p-arm have been identified with this technique. However, the resolution of CMA and the limitations of short-reads whole genome sequencing (WGS) technology do not allow the full characterization of the most complex chromosomal rearrangements. Herein, we report on two unrelated patients with a de novo 16p13.11p11.2 triplication associated with a 16p11.2 duplication, detected by CMA. These patients share a similar phenotype including hypotonia, severe neurodevelopmental delay with profound speech impairment, hyperkinetic behavior, conductive hearing loss, and distinctive facial features. Short-reads WGS could not map precisely any of the rearrangement’s breakpoints that lie within SDs. We used optical genome mapping (OGM) to determine the relative orientation of the triplicated and duplicated segments as well as the genomic positions of the breakpoints, allowing us to propose a mechanism involving recombination between allelic SDs and a NAHR event. In conclusion, we report a new clinically recognizable genomic disorder. In addition, the mechanism of these complex chromosomal rearrangements involving SDs could be unraveled by OGM.
Published: 2021

9. CNVxplorer: a web tool to assist clinical interpretation of CNVs in rare disease patients

Author: Francisco Requena, Patrick Nitschke, Valérie Malan, Antonio Rausell, Alejandro García, Hamza Hadj Abdallah, and Sergi Romana
Subjects: DNA Copy Number Variations, AcademicSubjects/SCI00010, MEDLINE, Gene Expression, Computational biology, Biology, Regulatory Sequences, Nucleic Acid, Genome, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Protein Interaction Mapping, Genetics, Animals, Humans, Copy-number variation, 030304 developmental biology, Epigenomics, Mice, Knockout, 0303 health sciences, Internet, Interpretation (logic), Genome, Human, 3. Good health, Workflow, Phenotype, Web Server Issue, 030217 neurology & neurosurgery, Software, Rare disease, Comparative genomic hybridization
Abstract: Copy Number Variants (CNVs) are an important cause of rare diseases. Array-based Comparative Genomic Hybridization tests yield a ∼12% diagnostic rate, with ∼8% of patients presenting CNVs of unknown significance. CNVs interpretation is particularly challenging on genomic regions outside of those overlapping with previously reported structural variants or disease-associated genes. Recent studies showed that a more comprehensive evaluation of CNV features, leveraging both coding and non-coding impacts, can significantly improve diagnostic rates. However, currently available CNV interpretation tools are mostly gene-centric or provide only non-interactive annotations difficult to assess in the clinical practice. Here, we present CNVxplorer, a web server suited for the functional assessment of CNVs in a clinical diagnostic setting. CNVxplorer mines a comprehensive set of clinical, genomic, and epigenomic features associated with CNVs. It provides sequence constraint metrics, impact on regulatory elements and topologically associating domains, as well as expression patterns. Analyses offered cover (a) agreement with patient phenotypes; (b) visualizations of associations among genes, regulatory elements and transcription factors; (c) enrichment on functional and pathway annotations and (d) co-occurrence of terms across PubMed publications related to the query CNVs. A flexible evaluation workflow allows dynamic re-interrogation in clinical sessions. CNVxplorer is publicly available at http://cnvxplorer.com., Graphical Abstract Graphical AbstractCNV annotation process and analyses offered by CNVxplorer together with its integration within the clinical workflow for genetic diagnosis of rare disease patients.
Published: 2021

10. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Author: Marie-Josèphe Tête, Matthias Hansen, Florie Lammens, Tobias Schäfer, Albert Bensman, Alexandra Cambier, Tobias B. Huber, Christoph J. Mache, Elisa Kuhn, Christian Brix Folsted Andersen, Corinne Isnard-Bagnis, Tarunveer S. Ahluwalia, Günter Klaus, Mathilda Bedin, Fabienne Jabot-Hanin, Julien Hogan, Laure Villoing-Gaudé, Timo Wagner, Patrick Nitschke, Carole Tournant, Marcus R. Benz, Maik Grohmann, Markus Gödel, Aude Servais, Corinne Antignac, Cécile Vigneau, Ferielle Louillet, Christine Bole-Feysot, Véronique Baudouin, Iseline Bouteau, Lars Pape, Kay Latta, Carsten Bergmann, Yong Li, Vincent Morinière, Saoussen Krid, Olivier Gribouval, Olivia Boyer, Bruno Ranchin, Anna Köttgen, Matias Simons, 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), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], School of Software (THSS), Tsinghua University [Beijing], Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de Néphrologie Rhumatologie Dermatologie, HCL Groupement Hospitalier Est-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de référence Maladies Rénales Rares, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'urologie, néphrologie et transplantation [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Pediatric Kidney, Hannover Medical School [Hannover] (MHH)-Children's Hospital, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Service de Génétique Médicale [CHU Necker], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), IT University of Copenhagen, NNF18OC0052457, Novo Nordisk Fonden, KO 3598/5-1,KIDGEM SFB1140 246781735, Deutsche Forschungsgemeinschaft, ANR-10-IAHU-01,ANR-14-ACHN-0013, Agence Nationale de la Recherche, 01GM1515C, Federal Ministry or Education and Research, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Tsinghua University [Beijing] (THU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-HCL Groupement Hospitalier Est-Centre de référence Maladies Rénales Rares, Service d'Urologie [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)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), IT University of Copenhagen (ITU), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and ANR-14-ACHN-0013,NEPHROFLY,Utilisation de Drosophila melanogaster pour étudier les maladies génétiques du rein(2014)
Subjects: Male, 0301 basic medicine, Nephrology, medicine.medical_specialty, Anemia, Megaloblastic, [SDV]Life Sciences [q-bio], Renal function, Receptors, Cell Surface, Kidney, urologic and male genital diseases, Gastroenterology, Kidney Tubules, Proximal, 03 medical and health sciences, 0302 clinical medicine, Focal segmental glomerulosclerosis, Malabsorption Syndromes, Internal medicine, Chronic kidney disease, medicine, Genetics, Albuminuria, Humans, Alport syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, Proteinuria, business.industry, urogenital system, Vitamin B 12 Deficiency, General Medicine, medicine.disease, Cubilin, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Female, Clinical Medicine, medicine.symptom, business, Nephrotic syndrome, Genetic diseases
Abstract: International audience; BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
Published: 2020

11. A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

Author: Yuriy Stepanovskiy, Liudmyla Chernyshova, Elfride De Baere, Davood Mansouri, Nima Parvaneh, Mahboubeh Mansouri, María Teresa Herrera, S. Alireza Mahdaviani, Fabienne Jabot-Hanin, Jacinta Bustamante, Mélanie Migaud, Laurent Abel, Anne Puel, Jérémie Rosain, Alejandro Nieto-Patlán, Frédéric Tores, Mehrnaz Mesdaghi, Emilie Corvilain, Gaspard Kerner, Virginie Grandin, Edna Venegas-Montoya, Capucine Picard, Stéphanie Boisson-Dupuis, Patrick Nitschke, Sigifredo Pedraza-Sánchez, Carmen Oleaga-Quintas, Stéphane Marot, Caroline Deswarte, Jean-Laurent Casanova, Christine Bole-Feysot, Hannah Verdin, Anastasia Bondarenko, Garyfallia Syridou, Maria Tsolia, Sara Elva Espinosa-Padilla, Nathalie Lambert, Corinne Jacques, Lizbeth Blancas-Galicia, and Marco Antonio Yamazaki-Nakashimada
Subjects: Male, 0301 basic medicine, DNA Copy Number Variations, Immunology, Gene Expression, Alu element, Locus (genetics), Biology, Genome, Article, Interferon-gamma, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, Interleukin-12 Receptor beta 1 Subunit, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Copy-number variation, Indel, Interleukin 12 receptor, beta 1 subunit, Alleles, Genetic Association Studies, Genetics, Mycobacterium Infections, Base Sequence, Chromosome Mapping, Pedigree, Phenotype, 030104 developmental biology, Mutation, Mendelian inheritance, symbols, Female
Abstract: PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variation by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on PHA-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, in either the homozygous state (n=1) or in trans (n=4) with a single nucleotide variation (n=3) or a small indel (n=1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
Published: 2018

12. Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract

Author: Olivier Alibeu, Cécile Jeanpierre, Marc Jeanpierre, Cécile Fourrage, Valérie Malan, Charline Henry, Robert Novo, Frédéric Tores, Vincent Morinière, Madeline Louise Reilly, Marc Bras, Sophie Saunier, Rémi Salomon, Corinne Antignac, Camille Humbert, Lara De Tomasi, Patrick Nitschke, Dominique Gaillard, Laurence Heidet, Marie Gonzales, Christine Pietrement, Jelena Martinovic, Joelle Roume, Christine Bole-Feysot, and Elise Schaefer
Subjects: 0301 basic medicine, Genetics, Candidate gene, Genetic heterogeneity, Kidney development, General Medicine, Disease, Biology, 03 medical and health sciences, 030104 developmental biology, Nephrology, Cancer research, Epigenetics, Gene, Loss function, Exome sequencing
Abstract: Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.
Published: 2017

13. Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

Author: Laurence Perrin, Céline Huber, Odile Boute, Christine Bole-Feysot, Pierre Bitoun, Yasemin Alanay, Patrick Nitschke, Beyhan Tüysüz, Chloé Quélin, E. Ranza, Cécile Masson, Geneviève Baujat, Christine Coubes, Valérie Cormier-Daire, Nicolas Levin, Nursel Elcioglu, Lihadh Al-Gazali, Paulien A Terhal, Laurence Faivre, Meriel McEntagart, Diana Johnson, Banu Güzel Nur, Philippe M. Campeau, Ercan Mihci, and Alper Gezdirici
Subjects: 0301 basic medicine, Spondyloepimetaphyseal dysplasia, business.industry, 030105 genetics & heredity, medicine.disease, Bioinformatics, Phenotype, Short stature, 3. Good health, 03 medical and health sciences, Catel–Manzke syndrome, Genetics, Etiology, Medicine, Larsen syndrome, Joint dislocation, medicine.symptom, 10. No inequality, business, Genetics (clinical), Exome sequencing
Abstract: The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
Published: 2017

14. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Author: Michel Polak, Catherine Strassel, Fabienne Jabot-Hanin, Claude Besmond, Frédéric Tores, Patrick Nitschke, Christine Bole-Feysot, Athanasia Stoupa, Carsten Janke, Anita Luise Michel, François Lanza, Dominique Lasne, Arnold Munnich, Frédéric Adam, Juliane Léger, Alexandre Kauskot, Alain Schmitt, Kathiresan Natarajan, Sanjay Gawade, Gabor Szinnai, Aurore Carré, Delphine Borgel, Dulanjalee Kariyawasam, Raphael Scharfmann, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, UMR-S1176, Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Basel (Unibas), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et Diabétologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Pancréas endocrine et diabète de l'enfant, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion (http://www.u949.inserm.fr/), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: 0301 basic medicine, Medicine (General), Pathology, endocrine system diseases, Platelet Aggregation, [SDV]Life Sciences [q-bio], Physiology, Gene mutation, QH426-470, Mice, TUBB1, Tubulin, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Research Articles, Mice, Knockout, Hematology, TUBB1 Subject Categories Genetics, Thyroid, congenital hypothyroidism, Congenital hypothyroidism, 3. Good health, medicine.anatomical_structure, Thyroid Dysgenesis, Molecular Medicine, Research Article, Blood Platelets, endocrine system, medicine.medical_specialty, Protein family, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Gene Therapy & Genetic Disease, Thyroid dysgenesis, 03 medical and health sciences, R5-920, Internal medicine, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Animals, Humans, Gene, Abnormal Platelet, macroplatelets, business.industry, mutations, medicine.disease, 030104 developmental biology, Mutation, Genetics, Gene Therapy & Genetic Disease, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Haematology
Abstract: The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
Published: 2019

15. Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Author: Michel Simonneau, Hassan Kisra, J. M. Moalic, Rim Roudies, Jean-Marc Plaza, Gabriel Santpere, Thomas Klarić, Wenqi Han, Christine Plancon, Mounia Bensaid, Patrick Nitschke, Imane Benhima, Nisrine Tarik, Nenad Sestan, Aude-Marie Lepagnol-Bestel, Jean-François Deleuze, and Yann Loe-Mie
Subjects: Proband, Genetics, biology, Locus (genetics), Disease gene identification, medicine.disease, Genetic analysis, mental disorders, biology.protein, medicine, Autism, TBR1, Copy-number variation, Exome sequencing
Abstract: Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype.Significance StatementThe human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type–specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.
Published: 2019
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16. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Author: Dana Ranta, Jean Donadieu, Pekka Jaako, Alan J. Warren, Etienne Lengliné, Laetitia Kermasson, Christine Bellanné-Chantelot, Angela Hoslin, Alexandre Faille, Hubert Ducou Le Pointe, Patrick Revy, Abraham Acevedo-Arozena, Christine Bole-Feysot, Caroline Kannengiesser, Blandine Beaupain, Shengjiang Tan, Patrick Nitschke, Odile Fenneteau, Jean-Pierre de Villartay, Stefano Fumagalli, Maryline Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, 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 Saint-Antoine [AP-HP], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], 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 de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National History Museum of London, Acevedo-Arozena, Abraham [0000-0001-6127-7116], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Hémato-oncologie Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint-Antoine [APHP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-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)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Male, Models, Molecular, Ribosomopathy, Protein Conformation, DNA Mutational Analysis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, Biochemistry, Ribosome, Mice, 0302 clinical medicine, Peptide Initiation Factors, Large ribosomal subunit, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Genetics, 0303 health sciences, Shwachman–Diamond syndrome, Mutation, Translation (biology), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Shwachman-Diamond Syndrome, 3. Good health, Pedigree, Phenotype, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, EIF6, 030220 oncology & carcinogenesis, Female, Disease Susceptibility, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Immunology, Mice, Transgenic, Biology, 03 medical and health sciences, Structure-Activity Relationship, Red Cells, Iron, and Erythropoiesis, medicine, Animals, Humans, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Whole Genome Sequencing, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Peptide Elongation Factors, Disease Models, Animal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ribosome Subunits, Genome-Wide Association Study
Abstract: Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
Published: 2019

17. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author: Fernando E. Sepulveda, Geneviève de Saint Basile, Patrick Nitschke, Stéphane Blanche, Maxime Battistella, David Michonneau, Nada Jabado, Shriya Deshmukh, David Mitchell, Christine Bole-Feysot, Janie Charlebois, Bénédicte Neven, Hamid Nikbakht, Mikko Taipale, Paul G Ekert, Christopher McCormack, William D. Foulkes, Leonie G. Mikael, Alexandrine Garrigue, Dzana Dervovic, Nancy Hamel, Andrea Bajic, Simon Gravel, Despina Moshous, Sharon Abish, Frank Sicheri, Rachel Conyers, Van-Hung Nguyen, Frédéric Guerin, Susan Kelso, Sylvie Fraitag, H. Miles Prince, Jean-Sebastien Diana, Rola Dali, Marianne Besnard, Jonathan Pratt, Elvis Terci Valera, Dong-Anh Khuong-Quang, Catherine Thieblemont, Alain Fischer, Tenzin Gayden, Jacek Majewski, Brigitte Bader-Meunier, Daniel Schramek, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children’s Cancer Center, The Royal Children’s Hospital and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics [Toronto], University of Toronto, Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, Canadian Centre for Computational Genomics, Montreal, Canada, Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Dermatology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia, Department of Oncology [Melbourne, Australie], Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia, Service d'immuno-hématologie pédiatrique [CHU Necker], epartment of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Laboratoire d'anatomie pathologique [CHU Necker], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], 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)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: 0301 basic medicine, Adult, Male, Panniculitis, Adolescent, T cell, [SDV]Life Sciences [q-bio], Biology, HAVCR2, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Germline mutation, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Exome Sequencing, Genetics, medicine, T-cell lymphoma, Humans, Genetic Predisposition to Disease, Child, Hepatitis A Virus Cellular Receptor 2, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hemophagocytic lymphohistiocytosis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Infant, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
Published: 2018

18. Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy

Author: Anne Guimier, Richard Redon, Agnès Delahodde, Christopher T. Gordon, Philippe Charron, Myriam Oufadem, Agnès Rötig, Alain Dautant, Patrick Nitschke, Stanislas Lyonnet, Damien Bonnet, Sylvie Di Filippo, Cécile Masson, Patrice Bouvagnet, Loïc de Pontual, Béatrice Kugener, François Godard, Nigel G. Laing, Christine Bole-Feysot, Vincent Probst, Jeanne Amiel, Christelle Vasnier, Stéphane Dauger, Gianina Ravenscroft, Caroline Rambaud, Cheryl Longman, Jean-Paul di Rago, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Center for Medical Research, University of Western Australia and the Harry Perkins Institute for Medical Research WA 6009, Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Stress Abiotiques et Différenciation des Végétaux Cultivés (SADV), Institut National de la Recherche Agronomique (INRA)-Université de Lille, Sciences et Technologies, Institut Charles Viollette (ICV) - EA 7394 (ICV), Université d'Artois (UA)-Institut National de la Recherche Agronomique (INRA)-Université du Littoral Côte d'Opale (ULCO)-Institut Supérieur d'Agriculture-Université de Lille, Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), 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), West of Scotland Regional Genetics Service, Physiologie integrée du système d'éveil, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR19-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Sommeil Pédiatrique (Hôpital Mère-Enfant), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Cardiogénétique, CHU de Lyon HCL-GH Est-Hôpital Louis Pradel, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Cardiologie Pédiatrique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU Pitié-Salpêtrière [AP-HP], Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche de l'institut du thorax (ITX-lab), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Sciences et Technologies-Institut National de la Recherche Agronomique (INRA), Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de la Recherche Agronomique (INRA)-Université d'Artois (UA)-Institut Supérieur d'Agriculture, 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), CHU Pitié-Salpêtrière [APHP], Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Heterozygote, Saccharomyces cerevisiae Proteins, [SDV]Life Sciences [q-bio], Mitochondrial disease, Mutant, Mutation, Missense, Saccharomyces cerevisiae, Mitochondrion, Biology, Compound heterozygosity, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, medicine, Humans, Missense mutation, Exome, Genetics(clinical), Alleles, Genetics (clinical), Membrane Potential, Mitochondrial, Genes, Essential, Microbial Viability, Genetic Complementation Test, Infant, Sudden cardiac arrest, Proton Pumps, medicine.disease, Mitochondria, Diphosphates, Inorganic Pyrophosphatase, Death, Sudden, Cardiac, 030104 developmental biology, Essential gene, Mutation, Female, medicine.symptom, Gene Deletion, 030217 neurology & neurosurgery, Orthologous Gene
Abstract: International audience; Sudden unexpected death in infancy occurs in apparently healthy infants and remains largely unexplained despite thorough investigation. The vast majority of cases are sporadic. Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family. PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell. We show that deletion of the orthologous gene in yeast (ppa2Δ) compromises cell viability due to the loss of mitochondria. Expression of wild-type human PPA2, but not PPA2 containing the mutations identified in affected individuals, preserves mitochondrial function in ppa2Δ yeast. Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria from the mutant yeast cells. Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants.
Published: 2016

19. Mutations inLTBP3cause acromicric dysplasia and geleophysic dysplasia

Author: Patricia Keith, Valérie Cormier-Daire, Christine Bole-Feysot, Carine Le Goff, Tony J. Kenna, Aideen M. McInerney-Leo, Cay M. Kielty, Emma L. Duncan, Paul Leo, Ruth Steer, Patrick Nitschke, Andreas Zankl, Jessica Harris, and Matthew A. Brown
Subjects: 0301 basic medicine, Heterozygote, Fibrillin-1, Limb Deformities, Congenital, Mutation, Missense, 030105 genetics & heredity, Biology, 03 medical and health sciences, Exon, Transforming Growth Factor beta, Acromicric dysplasia, Genetics, medicine, Humans, Missense mutation, Exome, Myhre syndrome, Genetics (clinical), Exome sequencing, Bone Diseases, Developmental, Microfilament Proteins, Brachydactyly, Exons, medicine.disease, Weill-Marchesani Syndrome, Phenotype, 030104 developmental biology, Latent TGF-beta Binding Proteins, Dysplasia, Mutation, Cancer research
Abstract: Background Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill–Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill–Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. Methods Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. Results A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure–a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). Conclusions The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
Published: 2016

20. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies

Author: Noelle Lachaussée, Géraldine Mollet, Maria Clara Guida, Olivier Gribouval, Olivia Boyer, Corinne Antignac, Thierry Billette de Villemeur, Martin Helmstädter, Caroline Nava, Rolf Bodmer, Alexandra Afenjar, Jane Juusola, Patrick Nitschke, Sara Gonçalves, Boris Keren, Patricia G. Wheeler, Marina Charbit, Tobias B. Huber, Marie-Claire Gubler, Julie Patat, Marlène Rio, Christelle Arrondel, Matias Simons, Christine Bole-Feysot, and Devon Haynes
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, lcsh:QH426-470, Adolescent, Heart Diseases, DNA Mutational Analysis, Corpus callosum, Bioinformatics, Cell Line, 03 medical and health sciences, Text mining, Cataracts, Genetics, medicine, Animals, Drosophila Proteins, Humans, Abnormalities, Multiple, p300-CBP Transcription Factors, Clinical phenotype, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Cells, Cultured, Proteinuria, biology, business.industry, Homozygote, Correction, medicine.disease, biology.organism_classification, Pedigree, lcsh:Genetics, 030104 developmental biology, Phenotype, ADD3, Nasal Diseases, Mutation, Kidney Failure, Chronic, Calmodulin-Binding Proteins, Drosophila, Female, medicine.symptom, Drosophila melanogaster, business
Abstract: Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
Published: 2018

21. Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies

Author: Maryse Bonnière, Férechté Encha-Razavi, Yves Ville, Lucile Boutaud, Laurence Colleaux, Charlotte Mechler, Patrick Nitschke, Valérie Cormier-Daire, Bettina Bessières, Judith de Oliveira, Philippe Roth, Linda Mouthon, Tania Attié-Bitach, Christine Bole, Nadia Bahi-Buisson, Nathalie Boddaert, Valérie Serre, Caroline Alby, Stanislas Lyonnet, Marlène Rio, Amale Ichkou, Sophie Thomas, Michel Vekemans, Christopher T. Gordon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), 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), CHU Necker - Enfants Malades [AP-HP], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Service de radiologie pédiatrique [CHU Necker], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Male, Candidate gene, Adolescent, Protein Conformation, Nerve Tissue Proteins, Biology, Corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Brain commissure, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Megalencephaly, Amino Acid Sequence, Child, Ear Diseases, Genetics (clinical), Exome sequencing, Zinc finger, Macrocephaly, Infant, Newborn, Brain, Calcinosis, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Sequence Analysis, DNA, medicine.disease, Primrose syndrome, 3. Good health, Pedigree, Muscular Atrophy, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Nucleic Acid Conformation, Female, medicine.symptom, Agenesis of Corpus Callosum, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.
Published: 2018

22. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome

Author: Asma Chebil, Duksha Ramful, Thibaud Jouan, Hanitra Randrianaivo, Norbert F. Ajeawung, Nicolas Gruchy, Yannis Duffourd, Bérénice Doray, Christopher T. Gordon, Francesca Filippini, Christine Bole-Feysot, Philippe M. Campeau, Asma Omarjee, Julien Thevenon, Paul Kuentz, Jean-Luc Alessandri, Patrick Nitschke, Laurence Faivre, Jeanne Amiel, Coralie Dumont, Thi Tuyet Mai Nguyen, Marion Gérard, Myriam Oufadem, Guillaume Benoist, Olivier Alibeu, Marie-Line Jacquemont, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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), CHU Sud Saint Pierre [Ile de la Réunion], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherche du CHU Sainte-Justine, CHU Sainte Justine [Montréal], Centre Hospitalier de Mayotte, 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, 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, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Service de réanimation néonatologique et pédiatrique [La Réunion], Groupe Hospitalier Sud-CHR La réunion, Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Pôle Gynécologie Obstétrique [CHM, Mayotte], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pôle Femme-Mère-Enfant [CHU La Réunion, Saint-Pierre, La Réunion], Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), 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 ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, 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 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 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire de Génétique Médicale ( LGM ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Université de Lausanne (UNIL), Laboratoire de Chimie Physique Macromoléculaire (LCPM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Equipe NuTox (LNC - U1231) (NUTOX), Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Maurice, Service de médecine foetale et foetopathologie, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), and University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC)
Subjects: 0301 basic medicine, Male, MESH: Limb Deformities, Congenital, Limb Deformities, Congenital, MESH: Phosphotransferases, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030105 genetics & heredity, Biology, MESH: Founder Effect, Article, 03 medical and health sciences, Pulmonary hypoplasia, 0302 clinical medicine, Fryns syndrome, Loss of Function Mutation, Genetics, medicine, Missense mutation, Humans, Allele, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Loss function, Hernia, Diaphragmatic, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Phosphotransferases, MESH: Infant, Newborn, Infant, Newborn, Congenital diaphragmatic hernia, Facies, Infant, MESH: Loss of Function Mutation, medicine.disease, MESH: Infant, Hypoplasia, Founder Effect, MESH: Male, MESH: Hernia, Diaphragmatic, MESH: Facies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Gene Deletion, Female, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Founder effect
Abstract: International audience; Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.
Published: 2018

23. Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Author: Said Lebbah, Emmanuelle Plaisier, Marieline Lison, Marie-Alice Macher, Pascale Hilbert, Karin Dahan, Marie-Claire Gubler, Laurence Heidet, Laure-Hélène Noël, Vincent Morinière, Alexandra Topa, Christine Bole-Feysot, Solenn Pruvost, Bertrand Knebelmann, Patrick Nitschke, and Corinne Antignac
Subjects: Adult, Collagen Type IV, Male, Heterozygote, medicine.medical_specialty, Adolescent, DNA Mutational Analysis, Genetic Counseling, Nephritis, Hereditary, Biology, urologic and male genital diseases, medicine.disease_cause, Autoantigens, Polymorphism, Single Nucleotide, DNA sequencing, Cohort Studies, Young Adult, symbols.namesake, Molecular genetics, medicine, Humans, Allele, Alport syndrome, Child, Indel, Family Health, Sanger sequencing, Genetics, Mutation, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Amplicon, medicine.disease, Basic Research, Phenotype, Nephrology, Child, Preschool, symbols, Female
Abstract: Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.
Published: 2014

24. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Author: Bertrand Isidor, Christelle Arrondel, Camille Humbert, Flora Silbermann, Marie-Hélène Said-Menthon, Cécile Jeanpierre, Christelle Cabrol, Audrey Desgrange, Frédéric Tores, Laurence Heidet, Lara De Tomasi, Ishwar C. Verma, Marie-Pierre Cordier, Ratna Dua Puri, Laurent Gavard, Jelena Martinovic, Christine Pietrement, Juliette Piard, Olivier Niel, Marie Gonzales, Patrick Nitschke, Robert Novo, Stéphane Fouquet, Joelle Roume, Philippe Khau Van Kien, Jacqueline Aziza, Pierre David, Sophie Saunier, Marie-Hélène Saint-Frison, Hubert Journel, Christine Bole-Feysot, The molecular basis of kidney diseases: cystinosis and hereditary nephrotic syndrome (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Coordination des Cellules et Morphogenèse / Heart Morphogenesis (Imagine - Institut Pasteur U1163), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Hôpital Robert Debré Paris, Hôpital Robert Debré, CHI Poissy-Saint-Germain, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and Sir Ganga Ram Hospital [New Delhi, India]
Subjects: 0301 basic medicine, Male, nephrogenesis, 030105 genetics & heredity, Kidney, Mice, Missense mutation, Exome, Child, Urinary Tract, Genetics (clinical), Exome sequencing, kidney development, Mice, Knockout, kidney agenesis, heart defect, tubulogenesis, Hypoplasia, Neoplasm Proteins, medicine.anatomical_structure, Phenotype, Agenesis, Female, Kidney Diseases, medicine.medical_specialty, Heterozygote, Urinary system, mouse model, Biology, Congenital Abnormalities, 03 medical and health sciences, Fetus, Internal medicine, Report, Genetics, medicine, Animals, Humans, Renal agenesis, CAKUT, Membrane Proteins, Proteins, genital tract, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, medicine.disease, 3DISCO, GREB1L, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Urogenital Abnormalities, Mutation, Kidney disease
Abstract: International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.
Published: 2017

25. A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis

Author: Fahd Almanjomi, Eman Al Idrissi, Capucine Picard, Nathalie Lambert, Patrick Nitschke, Gaël Ménasché, Mofareh Al Zahrani, Hamza Ali Alghamdi, Virginie Grandin, Fernando E. Sepulveda, Geneviève de Saint Basile, Murad K. Habazi, Hamoud Al-Mousa, Abdulaziz Al-Ghonaium, Christine Bole-Feysot, Centre d’Etudes des Déficits Immunitaires (CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Allergy and Immunology Section [Riyadh, Saudi Arabia] (Children Specialized Hospital), King Fahad Medical City [Riyadh, Saudi Arabia], Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], Plateforme de Génomique [Paris] (Fondation Imagine), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5), Contract grant sponsors: French National Institute of Health and Medical Research (INSERM), the Agence National de la Recherche (ANR) (HLH-Cytotox/ANR-12-BSV1-0020-01), the Fondation Imagine-Institut des Maladies Génétiques., Ménasché, Gaël, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Skin Pigmentation, rab27 GTP-Binding Proteins, Consanguinity, Gene duplication, Pigment accumulation, Griscelli syndrome, Genetics (clinical), Sequence Deletion, Genetics, Hypopigmentation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Homozygote, Piebaldism, Exons, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], founder effect, Codon, Nonsense, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Tandem exon duplication, Primary Immunodeficiency Diseases, Saudi Arabia, Biology, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Indel, Point mutation, RAB27A, Breakpoint, Immunologic Deficiency Syndromes, gene duplication, medicine.disease, 030104 developmental biology, Griscelli syndrome type 2, Mutation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Hair, T-Lymphocytes, Cytotoxic
Abstract: International audience; Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.
Published: 2017

26. Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation

Author: Olivier Hermine, Meriem Garfa-Traore, Christine Bole-Feysot, Arnold Munnich, Agnès Rötig, Floriane Petit, Anthony Drecourt, Metodi D. Metodiev, Nicolas Goudin, Isabelle Desguerre, Chris Ottolenghi, Joel Babdor, Michael Dussiot, Florence Habarou, Nathalie Boddaert, Valérie Serre, and Patrick Nitschke
Subjects: 0301 basic medicine, Neurodegeneration with brain iron accumulation, Iron, Lipoylation, Transferrin receptor, Mitochondrion, Article, 03 medical and health sciences, 0302 clinical medicine, Palmitoylation, Basal ganglia, Receptors, Transferrin, Genetics, medicine, Homeostasis, Humans, Amino Acid Sequence, Fibroblast, Genetics (clinical), Dystonia, Chemistry, Calcium-Binding Proteins, Transferrin, Brain, Fibroblasts, medicine.disease, Endocytosis, Cell biology, 030104 developmental biology, medicine.anatomical_structure, HEK293 Cells, Cell culture, Mutation, Nerve Degeneration, Carrier Proteins, 030217 neurology & neurosurgery, HeLa Cells
Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.
Published: 2017

27. FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases

Author: Floriane Petit, Agnès Delahodde, Cécile Masson, Christine Bole-Feysot, Anthony Drecourt, Fanny Mochel, Christelle Domange, Souad Gherbi, Josseline Kaplan, Sylvie Gerber, Delphine Dupin Deguine, Olivier Sterkers, Georges Challe, Crystel Bonnet, Myriam Oufadem, Laurence Jonard, Oriane Mercati, Laurence Mahieu, Agnès Rötig, Patrick Nitschke, Saber Masmoudi, Stanislas Lyonnet, Isabelle Mosnier, Didier Bouccara, Antoine Paul, Sandrine Marlin, Christelle Vasnier, Ines Ben Aissa, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Iron-Sulfur Proteins, Male, Mitochondrial Diseases, Fe-S cluster synthesis, [SDV]Life Sciences [q-bio], Mutant, Auditory neuropathy, 030105 genetics & heredity, chemistry.chemical_compound, iron-sulfur cluster, Gene expression, Hearing Loss, Central, Genetics (clinical), Genetics, Mitochondria, Pedigree, Complementation, Ferredoxin-NADP Reductase, FDXR, Child, Preschool, Female, inorganic chemicals, Adult, Saccharomyces cerevisiae Proteins, Adolescent, Mitochondrial disease, Iron, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, Young Adult, Atrophy, Biosynthesis, ARH1, Report, medicine, Humans, Amino Acid Sequence, iron overload, Genetic Complementation Test, DNA replication, medicine.disease, Optic Atrophy, 030104 developmental biology, chemistry, Mutation, Sequence Alignment
Abstract: Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.
Published: 2017

28. Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis

Author: André Paget, Philippe Nicoud, Charline Henry, Emilie Filhol, Sabine Leh, Fan Yang, Flora Silbermann, Jan Halbritter, Alexandre Benmerah, Arthur Gutter, Friedhelm Hildebrandt, Per M. Knappskog, Anne E.C. Mellgren, Heon Yung Gee, Richard Sandford, Cecilie Bredrup, Dominique Joly, Pauline Krug, Helge Boman, Sophie Saunier, Christine Bole-Feysot, Nurcan Cengiz, Heidi Haugland, Maxence S. Macia, Marion Delous, Damien Brackmann, Nayir Ahmet, Eyvind Rødahl, Andreas W. Sailer, Edward J. Oakeley, Bolan Linghu, Daniela A. Braun, Stefan Johansson, Albane A. Bizet, Patrick Nitschke, Pierre Saint Mézard, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), Universitätsklinikum Leipzig [Germany] (UKL), Haukeland University Hospital, University of Bergen (UiB), Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia (Equipe Inserm U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpitaux du Pays du Mont-Blanc, Førde Central Hospital [Førde, Norway] (FCH), Istanbul University, University of Cambridge [UK] (CAM), Baskent University, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Novartis Institutes for BioMedical Research (NIBR), and Benmerah, Alexandre
Subjects: 0301 basic medicine, Candidate gene, 030232 urology & nephrology, Cell Cycle Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, MAPKBP1, Kidney, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mice, 0302 clinical medicine, Spindle Poles, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Zebrafish, Genetics, Mice, Knockout, Cilium, Intracellular Signaling Peptides and Proteins, Kidney Diseases, Cystic, Phenotype, Pedigree, mitotic spindle, Signal Transduction, Adolescent, Mitosis, Late onset, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Young Adult, Nephronophthisis, retinitis pigmentosa, Ciliogenesis, Report, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Retinitis pigmentosa, medicine, Juvenile, Animals, Humans, digenism, Cilia, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, Alleles, WDR62, [SDV.GEN]Life Sciences [q-bio]/Genetics, Correction, Fibroblasts, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Fibrosis, Human genetics, Ciliopathy, Disease Models, Animal, ciliopathy, 030104 developmental biology, Gene Expression Regulation, nephronophthisis, Mutation, NIH 3T3 Cells, Kidney Failure, Chronic, MAP kinase, 030217 neurology & neurosurgery, DNA Damage
Abstract: International audience; Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
Published: 2017

29. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Author: Audrey Boutron, Florence Habarou, Nathalie Boddaert, Tobias B. Haack, Johannes A. Mayr, Richard J. Rodenburg, G. Christoph Korenke, Chris Ottolenghi, Coraline Grisel, Holger Prokisch, Dominique Chretien, Christine Bole-Feysot, Stefan Kölker, Agnès Delahodde, Ivan Nemazanyy, Monika Eisermann, Thomas Meitinger, Nicolas Goudin, Agnès Rötig, Robert Barouki, Iris Marquardt, Marine Madrange, Patrick Nitschke, Pascale de Lonlay, Clément Pontoizeau, Yamina Hamel, Tim M. Strom, Elise Lebigot, Cécile Laroche, René G. Feichtinger, Bernadette Chadefaux-Vekemans, Kanetee Busiah, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Eurecom [Sophia Antipolis], ISA NMR Methods for Metabolism - Methodes RMN en métabolomique (2014-2018), Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept Biochem, Universidade Federal de Pernambuco [Recife] (UFPE), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), 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), Unité de Biochimie Métabolique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Plateforme d'Imagerie Cellulaire [SFR Necker], Service de Radiologie et imagerie médicale [CHU Necker], Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie métabolique [CHU Necker], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Service de Biochimie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), NMR Methods for Metabolism - Methodes RMN en métabolomique, Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Technical University of Munich (TUM), Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum München = German Research Center for Environmental Health, and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Dehydrogenase, chemistry.chemical_compound, 0302 clinical medicine, Amino Acids, Genetics (clinical), Cells, Cultured, Brain Diseases, Brain Mapping, Glycine cleavage system, Thioctic Acid, Brain, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Pyruvate dehydrogenase complex, encephalopathy, metabolic flux, Magnetic Resonance Imaging, 3. Good health, Mitochondria, Lipoic acid, Biochemistry, α-oxoglutarate dehydrogenase, Leucine, Protein Binding, medicine.medical_specialty, Lipoylation, Glycine, Biology, 03 medical and health sciences, Oxygen Consumption, pyruvate dehydrogenase, Internal medicine, Report, Genetics, medicine, LIPT2, Humans, hyperglycinemia, Infant, Newborn, Lipt2, Encephalopathy, Hyperglycinemia, Lipoic Acid, Metabolic Flux, Pyruvate Dehydrogenase, α-oxoglutarate Dehydrogenase, lipoic acid, 030104 developmental biology, Endocrinology, chemistry, Atrophy, Branched-chain alpha-keto acid dehydrogenase complex, Energy Metabolism, 030217 neurology & neurosurgery, Acyltransferases, Protein lipoylation
Abstract: Item does not contain fulltext Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (alpha-oxoglutarate dehydrogenase [alpha-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, alpha-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, alpha-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
Published: 2017

30. XYLT1 Mutations in Desbuquois Dysplasia Type 2

Author: Beyhan Tüysüz, Céline Huber, Valérie Cormier-Daire, Christine Bole-Feysot, Catherine Bui, Jules G. Leroy, Geert Mortier, Yasemin Alanay, Arnold Munnich, Patrick Nitschke, 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), Genetics Unit, Department of Pediatrics Hacettepe, University School of Medicine, Ankara, Department of Medical Genetics, Ghent University [Belgium] (UGENT), Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Acibadem University Dspace, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ankara University School of Medicine [Turkey], and Universiteit Gent = Ghent University [Belgium] (UGENT)
Subjects: Male, Dwarfism, medicine.disease_cause, Craniofacial Abnormalities, Consanguinity, 0302 clinical medicine, Exome, Genetics(clinical), Child, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Homozygote, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Female, Proteoglycans, medicine.symptom, Adult, Joint Instability, DNA, Complementary, Adolescent, Xylosyltransferase, Biology, Short stature, Article, Bone and Bones, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Pentosyltransferases, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Ossification, Ossification, Heterotopic, Sequence Analysis, DNA, Fibroblasts, XYLT1, medicine.disease, Molecular biology, Polydactyly, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human medicine, 030217 neurology & neurosurgery, Microsatellite Repeats
Abstract: Desbuquois dysplasia (DBQD) is a severe condition characterized by short stature, joint laxity, and advanced carpal ossification. Based on the presence of additional hand anomalies, we have previously distinguished DBQD type 1 and identified CANT1 (calcium activated nucleotidase 1) mutations as responsible for DBQD type 1. We report here the identification of five distinct homozygous xylosyltransferase 1 (XYLT1) mutations in seven DBQD type 2 subjects from six consanguineous families. Among the five mutations, four were expected to result in loss of function and a drastic reduction of XYLT1 cDNA level was demonstrated in two cultured individual fibroblasts. Because xylosyltransferase 1 (XT-I) catalyzes the very first step in proteoglycan (PG) biosynthesis, we further demonstrated in the two individual fibroblasts a significant reduction of cellular PG content. Our findings of XYLT1 mutations in DBQD type 2 further support a common physiological basis involving PG synthesis in the multiple dislocation group of disorders. This observation sheds light on the key role of the XT-I during the ossification process.
Published: 2014
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31. Mutations in BOREALIN cause thyroid dysgenesis

Author: Athanasia Stoupa, Claude Besmond, Cyrille Ramond, Delphine Zenaty, Raphael Scharfmann, Christine Bole-Feysot, Dulanjalee Kariyawasam, William R. Taylor, Arnold Munnich, Sébastien Gaujoux, Laurence Hubert, Juliane Léger, Taylor M Monus, Patrick Nitschke, Nicolas Glaser, Frédéric Sebag, Aurore Carré, Michel Polak, Stanislas Lyonnet, and Manelle Gueriouz
Subjects: 0301 basic medicine, medicine.medical_specialty, Mutation, Missense, Mitosis, Cell Cycle Proteins, Biology, medicine.disease_cause, Thyroid dysgenesis, 03 medical and health sciences, Cell Movement, Internal medicine, Genetics, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Molecular Biology, Gene, Genetics (clinical), Exome sequencing, Mutation, Thyroid, High-Throughput Nucleotide Sequencing, General Medicine, Articles, medicine.disease, Congenital hypothyroidism, Pedigree, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Thyroid Dysgenesis, Female, PAX8
Abstract: Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.
Published: 2016

32. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Author: Sylvie Gerber, Eduardo Silva, Valérie Serre, Jean-Michel Rozet, Stanislas Lyonnet, Sylvain Hanein, Bénédicte Demeer, Ghislaine Plessis, P Calvas, Lionel Bretillon, Lucas Fares-Taie, Christine Bole, Nicola K. Ragge, Jill Clayton-Smith, Xavier Gérard, Arnold Munnich, Clarisse Baumann, Margaux Serey, Patrick Nitschke, Josseline Kaplan, Nicolas Chassaing, Kaplan, Josseline, and Rozet, Jean-Michel
Subjects: Male, Genetic Linkage, Retinoic acid, Genes, Recessive, Biology, medicine.disease_cause, Microphthalmia, chemistry.chemical_compound, symbols.namesake, Chromosome Segregation, Report, medicine, Genetics, Food and Nutrition, Humans, Microphthalmos, Missense mutation, Genetics(clinical), Genetics (clinical), Exome sequencing, Sanger sequencing, Mutation, Anophthalmia, Homozygote, Anophthalmos, Exons, Sequence Analysis, DNA, Aldehyde Dehydrogenase, Disease gene identification, medicine.disease, Aldehyde Oxidoreductases, Molecular biology, Introns, eye diseases, Pedigree, HEK293 Cells, chemistry, Alimentation et Nutrition, symbols, Female, Mutant Proteins, sense organs
Abstract: Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.
Published: 2013
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33. Exome Sequencing Identifies INPPL1 Mutations as a Cause of Opsismodysplasia

Author: Christine Bole-Feysot, Deborah Bartholdi, Heloísa G. dos Santos, Martine Le Merrer, Stavit A. Shalev, Valérie Cormier-Daire, Denise P. Cavalcanti, Joelle Roume, Eissa Faqeih, Zvi Borochowitz, Anne-Lise Delezoide, Andrea Superti-Furga, Amandine Frigo, Patrick Nitschke, Arnold Munnich, Céline Huber, University of Zurich, and Cormier-Daire, Valérie
Subjects: 2716 Genetics (clinical), 10039 Institute of Medical Genetics, 610 Medicine & health, Biology, Compound heterozygosity, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, 1311 Genetics, medicine, Genetics, Missense mutation, Genetics(clinical), Exome, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, Mutation, Ossification, medicine.disease, Stop codon, 030220 oncology & carcinogenesis, 570 Life sciences, biology, Opsismodysplasia, medicine.symptom
Abstract: Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.
Published: 2013
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34. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ('FILS syndrome')

Author: Patrick Nitschke, Marianne Debré, Anne Durandy, Capucine Picard, Geneviève de Saint Basile, Christine Bole-Feysot, Jana Pachlopnik Schmid, Annick Lim, Alain Fischer, Patrick Revy, Roxane Lemoine, Nadine Nehme, Laurence Legeai-Mallet, Valéry Cormier-Daire, Franck Debeurme, and Jean-Pierre de Villartay
Subjects: Male, DNA polymerase, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Consanguinity, Immunology and Allergy, Child, Poly-ADP-Ribose Binding Proteins, Growth Disorders, Polymerase, Genetics, 0303 health sciences, Mutation, biology, 030302 biochemistry & molecular biology, Genetic disorder, Syndrome, Pedigree, 3. Good health, Child, Preschool, Female, France, medicine.symptom, Adult, Adolescent, DNA repair, Immunology, Genes, Recessive, Short stature, Facial Bones, Young Adult, 03 medical and health sciences, medicine, Humans, Point Mutation, Gene, Cell Proliferation, Livedo Reticularis, 030304 developmental biology, Chromosomes, Human, Pair 12, Base Sequence, Point mutation, Immunologic Deficiency Syndromes, Brief Definitive Report, DNA Polymerase II, medicine.disease, G1 Phase Cell Cycle Checkpoints, Molecular biology, Body Height, Introns, body regions, Alternative Splicing, biology.protein
Abstract: Homozygous missense mutations in POLE1 caused an inherited disorder characterized by facial dysmorphism, immunodeficiency, livedo, and short stature., DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.
Published: 2012

35. Mosaic parental germline mutations causing recurrent forms of malformations of cortical development

Author: François Artiguenave, Jamel Chelly, Bettina Bessières, Imen Rejeb, Catherine Fallet-Bianco, Giuseppe Muraca, Catheline Vilain, Adrienne Elmorjani, Nadia Bahi-Buisson, Nicolas Lebrun, Hélène Maurey, Julia Lauer Zillhardt, Sylvie Odent, Yuri Musizzano, Karine Poirier, Nicole Philip, David Geneviève, Cécile Masson, Stanislas Lyonnet, Yoann Saillour, Robert Olaso, Jelena Martinovic, Jean-François Deleuze, Lucile Pinson, Lamia Ben Jemaa, François Rivier, Juliette Nectoux, Patrick Van Bogaert, Anne Boland, Fabienne Giuliano, Patrick Nitschke, Loic Broix, Nicolas Leboucq, Cherif Beldjord, Nicole Bigi, Olivier Dulac, 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), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 [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), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie et biologie cellulaire, Université de Montréal (UdeM)-Hôpital Sainte-Justine, CHU Necker - Enfants Malades [AP-HP], Service de Neurologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, CHU Pontchaillou [Rennes], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre Hospitalier Régional et Universitaire, Service de génétique médicale, Hôpital l'Archet, Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Génétique Médicale, Université libre de Bruxelles (ULB), Service Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire de 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)-Université Paris Descartes - Paris 5 (UPD5), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], 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, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], 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 Cochin [AP-HP], Hôpital Sainte-Justine-Université de Montréal, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Libre de Bruxelles [Bruxelles] (ULB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], 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], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Centre de Reference Epilepsies Rares-CHU Necker - Enfants Malades [AP-HP], NeuroSpin, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut d'imagerie biomédicale (I²BM), Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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, Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] ( PhyMedExp ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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, Adult, Male, Candidate gene, [SDV]Life Sciences [q-bio], Short Report, Biology, Bioinformatics, Germline, 03 medical and health sciences, Germline mutation, Genetics, Syntaxin, Humans, Exome, Sibling, Genetics (clinical), Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, [ SDV ] Life Sciences [q-bio], Mosaicism, Qa-SNARE Proteins, Malformation of cortical development, 3. Good health, Pedigree, Malformations of Cortical Development, 030104 developmental biology, Genetic Loci, Female
Abstract: International audience; To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD
Published: 2016

36. Refining the phenotype associated with CASC5 mutation

Author: Marc Abramowicz, Karine Siquier-Pernet, Patrick Nitschke, Christine Bole-Feysot, Myriam Abada-Dendib, Florine Verny, Malika Chaouch, Abdelkrim Saadi, Arnold Munnich, Laurence Colleaux, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie, CHU Ben Aknoun - Centre Hospitalo Universitaire de Ben Aknoun [Alger], Department of Medical Genetics [Bruxelles], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Hôpital Erasme (Bruxelles)
Subjects: 0301 basic medicine, Adult, Male, Microcephaly, DNA Mutational Analysis, Consanguinity, Biology, Short stature, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Family, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, medicine.disease, Founder Effect, 3. Good health, Pedigree, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Codon, Nonsense, Algeria, Mutation (genetic algorithm), Female, medicine.symptom, Microtubule-Associated Proteins, Founder effect
Abstract: Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.
Published: 2016

37. Mutation in PNPT1, which Encodes a Polyribonucleotide Nucleotidyltransferase, Impairs RNA Import into Mitochondria and Causes Respiratory-Chain Deficiency

Author: Nina Entelis, Arnold Munnich, Cécilia Altuzarra, Anne-Marie Mager-Heckel, Patrick Nitschke, Vanessa Vedrenne, Ivan Tarassov, Florence Chretien, Agnès Rötig, Nathalie Boddaert, Valérie Serre, Pascale de Lonlay, and Ali Gowher
Subjects: Male, Mitochondrial DNA, Mitochondrial Diseases, Adolescent, Mitochondrial translation, Mitochondrial intermembrane space, Mitochondrial disease, Biology, DNA, Mitochondrial, RNA Transport, 5S ribosomal RNA, Exon, RNA, Transfer, Report, medicine, Genetics, Humans, Genetics(clinical), Polynucleotide phosphorylase, Genetics (clinical), RNA, Brain, Exons, Hep G2 Cells, medicine.disease, Molecular biology, Magnetic Resonance Imaging, RNA, Ribosomal, Child, Preschool, Exoribonucleases, Mutation, Female, RNA Interference
Abstract: Multiple-respiratory-chain deficiency represents an important cause of mitochondrial disorders. Hitherto, however, mutations in genes involved in mtDNA maintenance and translation machinery only account for a fraction of cases. Exome sequencing in two siblings, born to consanguineous parents, with severe encephalomyopathy, choreoathetotic movements, and combined respiratory-chain defects allowed us to identify a homozygous PNPT1 missense mutation (c.1160A>G) that encodes the mitochondrial polynucleotide phosphorylase (PNPase). Blue-native polyacrylamide gel electrophoresis showed that no PNPase complex could be detected in subject fibroblasts, confirming that the substitution encoded by c.1160A>G disrupts the trimerization of the protein. PNPase is predominantly localized in the mitochondrial intermembrane space and is implicated in RNA targeting to human mitochondria. Mammalian mitochondria import several small noncoding nuclear RNAs (5S rRNA, MRP RNA, some tRNAs, and miRNAs). By RNA hybridization experiments, we observed a significant decrease in 5S rRNA and MRP-related RNA import into mitochondria in fibroblasts of affected subject 1. Moreover, we found a reproducible decrease in the rate of mitochondrial translation in her fibroblasts. Finally, overexpression of the wild-type PNPT1 cDNA in fibroblasts of subject 1 induced an increase in 5S rRNA import in mitochondria and rescued the mitochondrial-translation deficiency. In conclusion, we report here abnormal RNA import into mitochondria as a cause of respiratory-chain deficiency.
Published: 2012
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38. TCTN3 Mutations Cause Mohr-Majewski Syndrome

Author: Colin A. Johnson, Valérie Cormier-Daire, Maryse Bonnière, Christel Thauvin-Robinet, Soumaya Mougou-Zerelli, Annick Toutain, Sophie Saunier, Stanislas Lyonnet, Laurence Loeuillet, Bettina Bessières, Sophie Thomas, Christine Bole-Feysot, Marine Legendre, Marie-Anne Barthez, Yves Ville, Tania Attié-Bitach, Caroline Alby, Katarzyna Szymanska, Frédérique Jossic, Patrick Nitschke, Albert David, Dominique Gaillard, M. T. Yacoubi, Michel Vekemans, Férechté Encha-Razavi, and Arnold Munnich
Subjects: Adolescent, Foot Deformities, Congenital, Molecular Sequence Data, Ciliopathies, Joubert syndrome, Young Adult, Fetus, Report, Cerebellum, GLI3, medicine, Genetics, Humans, Exome, Hedgehog Proteins, Genetics(clinical), Sonic hedgehog, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, Cystic kidney, Base Sequence, biology, Homozygote, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Ciliary transition zone, Sequence Analysis, DNA, Orofaciodigital Syndromes, medicine.disease, Cleft Palate, Ciliopathy, Phenotype, Mutation, biology.protein, Apoptosis Regulatory Proteins, Hand Deformities, Congenital, Signal Transduction
Abstract: Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.
Published: 2012
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39. Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis

Author: Philippe Flahaut, Caroline Thalassinos, Anne-Marie Guerrot, Caroline Michot, Avinash Abhyankar, Céline Klein, Carine Le Goff, Jean-Laurent Casanova, Martine Le Merrer, Alice Duncombe, Geneviève Baujat, Stanislas Lyonnet, Alice Goldenberg, Patrick Nitschke, Arnold Munnich, Valérie Cormier-Daire, and Esther Kinning
Subjects: Adult, Male, medicine.medical_specialty, Candidate gene, Adolescent, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Molecular Sequence Data, Acrodysostosis, Thyrotropin, Biology, Osteochondrodysplasias, medicine.disease_cause, Short stature, Young Adult, Report, Intellectual Disability, Internal medicine, medicine, Genetics, Humans, Exome, Genetics(clinical), Child, PRKAR1A, Genetics (clinical), Exome sequencing, Mutation, Base Sequence, Dysostoses, Phosphodiesterase, Sequence Analysis, DNA, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Endocrinology, Parathyroid Hormone, Child, Preschool, Female, medicine.symptom, Signal Transduction
Abstract: Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368∗]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368∗] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.
Published: 2012
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40. An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

Author: Wassila Carpentier, Isabelle Callebaut, Capucine Picard, Nada Jabado, Patrick Revy, Alain Fischer, Fabien Touzot, Laetitia Kermasson, Nathalie Lambert, Tangui Le Guen, Marina Cavazzana, Patrick Nitschke, Jean Soulier, Chantal Lagresle-Peyrou, Jean-Pierre de Villartay, Annick Lim, Christine Bole-Feysot, Isabelle André-Schmutz, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC-BT 502 INSERM, Departement de Biotherapie, the Study Center of Primary Immunodeficiencies, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Bioinformatique, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), INSERM U944 Laboratoire de Pathologie et Virologie Moléculaire, Laboratoire de Pathologie et Virologie Moléculaire, the Genome Quebec Innovation Centre, McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), 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 ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Institut Pasteur [Paris], Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de recherche pour le développement [IRD] : UR206, McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Biology, Lymphopenia, MYSM1, medicine, Immunology and Allergy, Gene silencing, Missense mutation, Humans, histone deubiquitinase, MYB, Transcription factor, Gene, Genetics, B-Lymphocytes, Hematopoietic stem cell homeostasis, [ SDV ] Life Sciences [q-bio], Lymphocyte differentiation, Immunologic Deficiency Syndromes, Hematopoietic stem cell, Infant, Cell Differentiation, genetic reversion, 3. Good health, Hematopoiesis, DNA-Binding Proteins, medicine.anatomical_structure, Mutation, Trans-Activators, Ubiquitin-Specific Proteases, immunodeficiency, Transcription Factors
Abstract: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119- monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives: We sought to characterize the underlying genetic cause of this syndrome. Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.
Published: 2015

41. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study

Author: Melissa T. Carter, Ed Blair, Evan A. Boyle, Yoko Narumi-Kishimoto, Sarah Ahmed, Lorenzo Tattini, Sarah Collins, Davide Mei, Patrick Nitschke, Jamel Chelly, Valerio Conti, Amy Goldstein, Renzo Guerrini, Ghayda M. Mirzaa, Allison L. Goetsch, Kathreen Johnston, Jay Shendure, Catharine Harris, Carissa Olds, Christopher Barnett, Kathryn Friend, Andrew E. Timms, Beth Martin, Anne Slavotinek, Jean-François Deleuze, Elena Parrini, William B. Dobyns, Christopher D. Smyser, Robert B. Hufnagel, and Sarah Barnett
Subjects: Adolescent, Population, DNA Mutational Analysis, Biology, Bioinformatics, medicine.disease_cause, DNA sequencing, Article, MPPH syndrome, 03 medical and health sciences, Young Adult, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Intellectual Disability, Polymicrogyria, medicine, megalencephaly, Missense mutation, Humans, Abnormalities, Multiple, Congenital bilateral perisylvian syndrome, polymicrogyria, education, Child, 030304 developmental biology, Genetic testing, Genetics, 0303 health sciences, education.field_of_study, Mutation, medicine.diagnostic_test, Infant, PIK3R2, medicine.disease, Perisylvian polymicrogyria, 3. Good health, Malformations of Cortical Development, mosaicism, Child, Preschool, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Summary Background Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment, and epilepsy. The causes of BPP are heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic causes of BPP and characterise their frequency in this population. Methods Children (aged ≤18 years) with polymicrogyria were enrolled into our research programme from July, 1980, to October, 2015, at two centres (Florence, Italy, and Seattle, WA, USA). We obtained samples (blood and saliva) throughout this period at both centres and did whole-exome sequencing on DNA from eight trios (two parents and one affected child) with BPP in 2014. After the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 by two methods in a cohort of 118 children with BPP. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal to large head size. Second, we did amplicon sequencing of the recurrent PIK3R2 mutation (Gly373Arg) in 80 children with various types of polymicrogyria including BPP. One additional patient had clinical whole-exome sequencing done independently, and was included in this study because of the phenotypic similarity to our cohort. Findings We identified a mosaic mutation (Gly373Arg) in a regulatory subunit of the PI3K-AKT-mTOR pathway, PIK3R2 , in two children with BPP. Of the 38 patients with BPP and normal to large head size who underwent targeted next-generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient had the recurrent PIK3R2 mutation identified by clinical whole-exome sequencing. Seven of these 20 patients had BPP alone, and 13 had BPP in association with features of the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. 19 patients had the same mutation (Gly373Arg), and one had a nearby missense mutation (Lys376Glu). Mutations were constitutional in 12 patients and mosaic in eight patients. In patients with mosaic mutations, we noted substantial variation in alternate (mutant) allele levels, ranging from ten (3%) of 377 reads to 39 (37%) of 106 reads, equivalent to 5–73% of cells analysed. Levels of mosaicism varied from undetectable to 37 (17%) of 216 reads in blood-derived DNA compared with 2030 (29%) of 6889 reads to 275 (43%) of 634 reads in saliva-derived DNA. Interpretation Constitutional and mosaic mutations in the PIK3R2 gene are associated with developmental brain disorders ranging from BPP with a normal head size to the MPPH syndrome. The phenotypic variability and low-level mosaicism, which challenge conventional molecular methods, have important implications for genetic testing and counselling. Funding US National Institutes of Health.
Published: 2015

42. Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

Author: Michael Nicouleau, Giulia Barcia, Mélanie Parisot, Arnold Munnich, Laurence Colleaux, Christine Bole-Feysot, Vincent Cantagrel, Isabelle Desguerre, Patrick Nitschke, Nathalie Boddaert, Nadia Bahi-Buisson, Cécile Masson, Daniel Medina-Cano, Marlène Rio, Hisham Megahed, Karine Siquier-Pernet, Clinical Genetics Department [Dokki, Egypt], Human Genetics and Genome Research Division [Dokki, Egypt]-National Research Center [Dokki, Egypt], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Service de neurologie pédiatrique [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), Service de Génétique Médicale [CHU Necker], Service de radiologie pédiatrique [CHU Necker], ANR-12-PDOC-0026,CerID-Gene,Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse(2012), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Université Sorbonne Paris Cité (USPC), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], ANR-12-PDOC-0026,CerID-Gene,Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse ( 2012 ), ANR-10-IAHU-0001/10-IAHU-0001,Imagine,Imagine ( 2010 ), BMC, BMC, Retour Post-Doctorant - Mécanismes génétiques et physiopathologiques responsables de déficiences intellectuelles associées à une malformation cérébelleuse - - CerID-Gene2012 - ANR-12-PDOC-0026 - PDOC - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Male, 0301 basic medicine, Proband, Exome sequencing, Developmental Disabilities, [SDV]Life Sciences [q-bio], Intellectual disability, 0302 clinical medicine, Exome, Genetics(clinical), Pharmacology (medical), Molybdenum cofactor deficiency, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, KIF1A, Genetics, Medicine(all), MOCS2, Brain, General Medicine, Magnetic Resonance Imaging, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Child, Preschool, Cerebellum atrophy, Female, Cerebellar atrophy, medicine.symptom, Cerebellar Ataxia, Biology, 03 medical and health sciences, Atrophy, medicine, Humans, Cerebellar ataxia, [ SDV ] Life Sciences [q-bio], Research, Sequence Analysis, DNA, medicine.disease, Human genetics, Early Diagnosis, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030217 neurology & neurosurgery
Abstract: Background Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don’t suggest a specific molecular diagnosis. Methods To genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models. Results We successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject. Conclusions This study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0436-9) contains supplementary material, which is available to authorized users.
Published: 2015

43. Author Correction: Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author: Catherine Thieblemont, Janie Charlebois, Daniel Schramek, Jean-Sebastien Diana, Tenzin Gayden, Van-Hung Nguyen, Patrick Nitschke, Rachel Conyers, Nancy Hamel, Frédéric Guerin, Christine Bole-Feysot, Sylvie Fraitag, William D. Foulkes, Frank Sicheri, Leonie G. Mikael, Sharon Abish, Hamid Nikbakht, Rola Dali, Stéphane Blanche, Fernando E. Sepulveda, Geneviève de Saint Basile, Alain Fischer, Marianne Besnard, Christopher McCormack, Andrea Bajic, Susan Kelso, Jacek Majewski, H. Miles Prince, Simon Gravel, David Michonneau, Nada Jabado, Shriya Deshmukh, Brigitte Bader-Meunier, Maxime Battistella, Bénédicte Neven, Jonathan Pratt, Dong-Anh Khuong-Quang, Elvis Terci Valera, Dzana Dervovic, Paul G Ekert, Alexandrine Garrigue, Despina Moshous, David Mitchell, and Mikko Taipale
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.anatomical_structure, T cell, Genetics, Cancer research, medicine, Biology, HAVCR2, Panniculitis, medicine.disease, Germline
Abstract: In the version of this article originally published, the main-text sentence “In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor” misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.
Published: 2018

44. Cakutome, a high-throughput tool for molecular diagnosis and identification of novel causative genes for CAKUT patients

Author: Cécile Jeanpierre, Olivier Alibeu, Charline Henry, E. Schaeffer, Christine Bole-Feysot, Robert Novo, Rémi Salomon, Christine Pietrement, R. Campait, Jelena Martinovic, Joelle Roume, Patrick Nitschke, Marie Gonzales, L. De Tomasi, Dominique Gaillard, Laurence Heidet, Sophie Saunier, Corinne Antignac, Cécile Fourrage, and Vincent Morinière
Subjects: Sanger sequencing, Biallelic Mutation, Genetics, Mutation, Candidate gene, Genetic heterogeneity, Biology, HNF1B, medicine.disease_cause, symbols.namesake, Pediatrics, Perinatology and Child Health, symbols, medicine, Copy-number variation, Exome sequencing
Abstract: Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of renal failure in children. CAKUT are phenotypically and genetically heterogeneous and more than 50 genes have been reported as mutated in patients. The most frequently mutated genes are those encoding transcription factors HNF1B, PAX2, EYA1 and SIX1. Most of the other genes are only mutated in a few patients and their implication is sometimes elusive. Methods We developped a targeted exome sequencing strategy («CAKUTOME», sureselect Agilent) focusing on 330 genes, including known validated or likely causative CAKUT genes, as well as candidate genes. A total of 215 unrelated patients were analysed, including 50 who had previously been tested for HNF1B, PAX2, EYA1 and/or SIX1 mutations by Sanger sequencing. Results/discussion/conclusion This approach proved to be an efficient and cost-effective strategy to identify pathogenic mutations and copy number variations in known CAKUT genes. The 25/165 rate of mutation we identified in HNF1B, PAX2, EYA1 or SIX1 is similar to the one obtained by Sanger sequencing. In addition, we identified heterozygous mutations in ANOS1 (Kallmann syndrome), GATA3 (hypoparathyroidism, deafness and kidney disease), or CHD7 (Charge syndrome), and biallelic mutation in KIF14 in 2, 3, 1 and 2 cases, respectively. Our data also led to the identification of a novel CAKUT gene, the mutation/deletion of which affected 5 unrelated cases in the cohort. Moreover, we identified variants in several other genes never reported as mutated in CAKUT patients, whose pathogenicity is being tested. Finally, no relevant variant was identified in 40 % of our series. Although mutations in gene(s), non-coding regions or microRNAs not targeted in our CAKUTOME could be involved in some of these cases, complex inheritance, somatic events, and/or environmental factors or epigenetic mechanisms likely explain this large fraction of cases.
Published: 2017

45. Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome

Author: Kevin Piquand, Nadia Elkhartoufi, Patrick Nitschke, Sophie Saunier, Meriem Garfa-Traore, Mathilde Nizon, Caroline Alby, Céline Huber, Marine Legendre, Bettina Bessières, Françoise Clerget-Darpoux, Valérie Cormier-Daire, Fanny Pelluard, Ferechté Encha-Ravazi, Arnold Munnich, André Mégarbané, Nicole Laurent, Tania Attié-Bitach, Salima El Chehadeh-Djebbar, Melinda Zombor, Sophie Thomas, Georges Abi-Tayeh, Laurence Faivre, Amale Ichkou, Michel Vekemans, Hajnalka Szabó, Christine Bole, Marion Failler, Stanislas Lyonnet, and László Sztriha
Subjects: Heart Defects, Congenital, Molecular Sequence Data, Cell Cycle Proteins, Biology, Short Rib-Polydactyly Syndrome, Ciliopathies, 03 medical and health sciences, Fatal Outcome, Ciliogenesis, Report, GLI3, Genetics, medicine, Humans, Genetics(clinical), Europe, Eastern, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Likelihood Functions, Short rib – polydactyly syndrome, Polydactyly, Base Sequence, Cilium, 030305 genetics & heredity, Sequence Analysis, DNA, medicine.disease, Phenotype, Human genetics, Hedgehog signaling pathway, Founder Effect, Pedigree, Codon, Nonsense, Centriolar satellite, Erratum, Hand Deformities, Congenital, Ciliary Motility Disorders, Hydrocephalus
Abstract: KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.
Published: 2015

46. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

Author: Juliette Nectoux, Rafael de Cid, Sylvain Baulande, France Leturcq, Jon Andoni Urtizberea, Isabelle Penisson-Besnier, Aleksandra Nadaj-Pakleza, Carinne Roudaut, Audrey Criqui, Lucie Orhant, Delphine Peyroulan, Raba Ben Yaou, Isabelle Nelson, Anna Maria Cobo, Marie-Christine Arné-Bes, Emmanuelle Uro-Coste, Patrick Nitschke, Mireille Claustres, Gisèle Bonne, Nicolas Lévy, Jamel Chelly, Isabelle Richard, Mireille Cossée, Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génopole [Evry], Université d'Évry-Val-d'Essonne (UEVE), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Nantes-Angers, Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Service de neurologie [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), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), 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), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Nowak, Cécile, and Centre de Recherche en Myologie
Subjects: Adult, Male, Screening techniques, Ubiquitin-Protein Ligases, ASTN2 Gene, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscular dystrophy, Gene, Genetics (clinical), Loss function, 030304 developmental biology, Family Health, Comparative Genomic Hybridization, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Massive parallel sequencing, Base Sequence, Breakpoint, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, Pedigree, Muscular Dystrophies, Limb-Girdle, Female, Gene Deletion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment.
Published: 2015

47. Uveal melanoma hepatic metastases mutation spectrum analysis using targeted next-generation sequencing of 400 cancer genes

Author: C Burin des Roziers, Armelle Luscan, Michel Vidaud, Eric Pasmant, Patrick Nitschke, A. Briand, Pierre-Alexandre Just, P Goussard, Benoit Terris, and Marie-Françoise Avril
Subjects: Uveal Neoplasms, DNA Mutational Analysis, Mutation, Missense, Biology, medicine.disease_cause, Cellular and Molecular Neuroscience, medicine, Missense mutation, Humans, Melanoma, Exome sequencing, Retrospective Studies, Genetics, Mutation, BAP1, GNA11, Liver Neoplasms, Cancer, High-Throughput Nucleotide Sequencing, medicine.disease, Sensory Systems, Neoplasm Proteins, Ophthalmology, Carcinogenesis, GNAQ, Genes, Neoplasm
Abstract: Aims Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features. Methods We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes. Results Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7 . The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes. Conclusions Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies.
Published: 2014

48. Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome

Author: Didier Lacombe, Séverine Bacrot, Niklas Feldhahn, Florence Petit, Mathilde Doyard, Daphné Lehalle, Patrick Nitschke, Arnold Munnich, Marie-Paule Vazquez, Olivier Alibeu, Céline Huber, Sandrine Marlin, and Valérie Cormier-Daire
Subjects: Adult, Male, Spliceosome, Heterozygote, Adolescent, Micrognathism, Mutation, Missense, Ribs, Biology, snRNP Core Proteins, Exon, symbols.namesake, Young Adult, Intellectual Disability, Genetics, Humans, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, Sanger sequencing, Base Sequence, Alternative splicing, Molecular biology, Child, Preschool, RNA splicing, symbols, Small nuclear ribonucleoprotein
Abstract: Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations.
Published: 2014

49. A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS

Author: Stéphanie Woerner, Laurent Daniel, Marie-Claire Gubler, Géraldine Mollet, Sophie Thomas, Guillaume Canaud, Sophie Saunier, Corinne Antignac, Evelyne Huynh Cong, Marie-Noëlle Peraldi, Patrick Nitschke, Jamil Hachicha, Nasr Ben Dhia, Marjolaine Willems, Albane A. Bizet, Christelle Arrondel, Flora Silbermann, Christine Bole-Feysot, Kais Harzallah, Laure-Hélène Noël, Emilie Filhol, Daouia Iftene, Olivier Gribouval, and Olivia Boyer
Subjects: Adult, Male, Adolescent, Mutation, Missense, Biology, medicine.disease_cause, Podocyte, Gene product, Mice, Young Adult, Nephronophthisis, Stress Fibers, Up Front Matters, medicine, Missense mutation, Animals, Humans, Cilia, Child, Adaptor Proteins, Signal Transducing, Cell Line, Transformed, Genetics, Family Health, Gene knockdown, Mutation, Glomerulosclerosis, Focal Segmental, Podocytes, Cilium, Homozygote, General Medicine, medicine.disease, Cell biology, Pedigree, medicine.anatomical_structure, Phenotype, Haplotypes, Nephrology, Female, Kidney disorder, Brief Communications, Microtubule-Associated Proteins
Abstract: Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.
Published: 2014

50. HGCS: an online tool for prioritizing disease-causing gene variants by biological distance

Author: Jean-Laurent Casanova, Lluis Quintana-Murci, Avinash Abhyankar, Bertrand Boisson, Laurent Abel, Mark Mazel, Patrick Nitschke, Stéphanie Boisson-Dupuis, Yuval Itan, Shen-Ying Zhang, Benjamin Mazel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Bio-informatic, New York Genome Center, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Unité d'Immunologie-Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunology, Medicine and Translational Research, Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health (NIH) Grant 8 UL1 TR000043., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The Rockefeller University, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and BMC, Ed.
Subjects: Candidate gene, Genomics, Computational biology, Web Browser, Biology, Computational and Statistical Genetics, User-Computer Interface, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Databases, Genetic, Genetics, Humans, Genetic Association Studies, Computational genomics, Computational Biology, Reproducibility of Results, Phenotype, Human genetics, 3. Good health, ComputingMethodologies_PATTERNRECOGNITION, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ComputingMethodologies_GENERAL, DNA microarray, Functional genomics, Software, Biotechnology
Abstract: International audience; BACKGROUND: Identifying the genotypes underlying human disease phenotypes is a fundamental step in human genetics and medicine. High-throughput genomic technologies provide thousands of genetic variants per individual. The causal genes of a specific phenotype are usually expected to be functionally close to each other. According to this hypothesis, candidate genes are picked from high-throughput data on the basis of their biological proximity to core genes -- genes already known to be responsible for the phenotype. There is currently no effective gene-centric online interface for this purpose. RESULTS: We describe here the human gene connectome server (HGCS), a powerful, easy-to-use interactive online tool enabling researchers to prioritize any list of genes according to their biological proximity to core genes associated with the phenotype of interest. We also make available an updated and extended version for all human gene-specific connectomes. The HGCS is freely available to noncommercial users from: http://hgc.rockefeller.edu/. CONCLUSIONS: The HGCS should help investigators from diverse fields to identify new disease-causing candidate genes more effectively, via a user-friendly online interface.
Published: 2014

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