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1. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

Author

Damien Haye, Sandrine Vonwill, Rolph Pfundt, Annick Toutain, Stephan C. Collins, Joost Kummeling, Sylviane Marouillat, Marie-Pierre Moizard, Médéric Jeanne, Dévina C. Ung, Binnaz Yalcin, Frédéric Laumonnier, Nora Chelloug, Tjitske Kleefstra, Marie-Laure Vuillaume, Valerie E. Vancollie, and Christel Wagner

Subjects
0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, 030305 genetics & heredity, Neurogenesis, Hippocampus, Hippocampal formation, medicine.disease, Phenotype, Cell biology, 03 medical and health sciences, Histone, Neurodevelopmental disorder, 22q11 Deletion Syndrome, Genetics, biology.protein, medicine, Haploinsufficiency, Genetics (clinical), 030304 developmental biology
Abstract

Item does not contain fulltext The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira(+/-) mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira(+/-) mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.

Published
2021

2. A novel mutation in the cleavage site N291 of TDP-43 protein in a familial case of amyotrophic lateral sclerosis

Author

Christian R. Andres, Frédéric Laumonnier, Patrick Vourc'h, Hélène Blasco, Stéphane Beltran, Philippe Corcia, and Anna A. Chami

Subjects
Biology, Cleavage (embryo), 03 medical and health sciences, Familial case, 0302 clinical medicine, Mutant protein, mental disorders, medicine, Humans, Dementia, Viability assay, Amyotrophic lateral sclerosis, Motor Neurons, Binding protein, Amyotrophic Lateral Sclerosis, Brain, nutritional and metabolic diseases, medicine.disease, nervous system diseases, DNA-Binding Proteins, Neurology, Cytoplasm, Mutation, Cancer research, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Cytoplasmic aggregation of TAR-DNA binding protein (TDP-43) in Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) is associated with post-translational modifications (PTM) and delocalization. Studies on postmortem brains of ALS and FTLD patients showed the existence of TDP-43 fragments that end at position N291. We report a new heterozygous mutation p.N291H in a familial case of ALS. Expression of the mutant protein in cell lines and primary motor neurons induces aggregate formation in the cytoplasm and reduces cell viability. The discovery of mutations at cleavage sites in TDP-43 in patients, which we reviewed here, is valuable for understanding the true role of the various TDP-43 fragments identified in patients and thus, for developing effective targeted therapies for ALS and FTLD treatment.

Published
2020

3. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author

Sylviane Marouillat, Marie-Laure Vuillaume, Thomas Smol, Rose-Anne Thépault, Lyse Ruaud, Sarah Grotto, Jamal Ghoumid, Nicolas Chatron, Annick Toutain, Marianne Till, Alain Verloes, Manon Dixneuf, Valérie Chune, Gaetan Lesca, Frédéric Laumonnier, Nathalie Couque, Bénédicte Gérard, Martine Raynaud, Judith Halewa, Dévina C. Ung, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ANR-20-CE17-0006,ASDecode,Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux(2020), Laumonnier, Frédéric, Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux - - ASDecode2020 - ANR-20-CE17-0006 - AAPG2020 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV]Life Sciences [q-bio], Mutation, Missense, autism spectrum disorder, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, functional analyses, PTCHD1 (patched domain containing 1) gene, 03 medical and health sciences, Mice, in vitro cellular models, subcellular localization, Genetics, medicine, Missense mutation, Animals, Humans, Gene, Genetics (clinical), Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Endoplasmic reticulum, 030305 genetics & heredity, Cell Membrane, Membrane Proteins, Subcellular localization, medicine.disease, In vitro, Transmembrane protein, Amino acid, [SDV] Life Sciences [q-bio], chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, missense variants, Research Article
Abstract

The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD., Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.

Published
2021

4. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Author

Stéphane Bézieau, Médéric Jeanne, Anne Sophie Denommé-Pichon, Jason Laufman, William B. Dobyns, Sébastien Küry, Judith Halewa, Elliott H. Sherr, Dominique Bonneau, Julie Vogt, Sophie Blesson, Hélène Demory, Jérôme Honnorat, Helene Cox, Séverine Audebert-Bellanger, Marie Laure Vuillaume, Sylviane Marouillat, Estelle Colin, Avgi Andreou, Emanuela Argilli, Bertrand Isidor, Bernhard Lohkamp, Miroslava Hancarova, Rajesh Khanna, Davit Babikyan, Sarka Bendova, Kimberly A. Aldinger, Aubin Moutal, Saskia M. Maas, Marjon van Slegtenhorst, Annick Toutain, Sylvie Odent, Rose Anne Thépault, Natella Kostandyan, Eleina M. England, Zdenek Sedlacek, Richard Redon, M. Mahdi Motazacker, Frédéric Laumonnier, Brigitte Gilbert-Dussardier, Grazia M.S. Mancini, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Arizona, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Birmingham Women's and Children's NHS Foundation Trust, University of Akron, Yerevan State Medical University after Mkhitar Heratsi, Charles University [Prague] (CU), Center for Integrative Brain Research, University of Washington [Seattle], University of California [Los Angeles] (UCLA), University of California (UC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], National Human Genome Research Institute, Ministry of Health of the Czech Republic, DGOS, Wellcome Trust, Chard-Hutchinson, Xavier, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Amsterdam UMC, University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Genetics, 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 ), Human Genetics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
Models, Molecular, Male, 0301 basic medicine, Hydrolases, [SDV]Life Sciences [q-bio], Hippocampal formation, Medical and Health Sciences, 0302 clinical medicine, Neurodevelopmental disorder, Tubulin, Models, Neurotrophic factors, Cerebellum, Intellectual disability, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, dendrite branching, Genetics (clinical), de novo missense variants, Pediatric, Genetics & Heredity, DPYSL5, Biological Sciences, [SDV] Life Sciences [q-bio], corpus callosum agenesis, Mental Health, Child, Preschool, Neurological, Female, Microtubule-Associated Proteins, Adult, Neurite, Intellectual and Developmental Disabilities (IDD), primary neuronal cultures, Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Rare Diseases, Mediator, Report, Intellectual Disability, Genetics, medicine, Humans, Preschool, Corpus Callosum Agenesis, brain malformation, Neurosciences, Molecular, medicine.disease, neurodevelopmental disorder, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Missense, Agenesis of Corpus Callosum, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Published
2021

5. LIMK2-1 is a Hominidae-Specific Isoform of LIMK2 Expressed in Central Nervous System and Associated with Intellectual Disability

Author

Sylviane Marouillat, Rose-Anne Thépault, Frédéric Laumonnier, Annick Toutain, Patrick Vourc'h, H. Cubéros, Béatrice Vallée, Hélène Bénédetti, Martine Raynaud, Christian R. Andres, Frédérique Bonnet-Brilhault, Julie Tastet, University Medical Center [Utrecht], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Equipe neurogénétique et neurométabolomique, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), German Aerospace Center (DLR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Central Nervous System, Models, Molecular, 0301 basic medicine, Gene isoform, Neurite, [SDV]Life Sciences [q-bio], Neuronal Outgrowth, Phosphatase, Central nervous system, Mutation, Missense, Sequence Homology, Biology, Lim kinase, Mice, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Intellectual disability, medicine, Animals, Protein Isoforms, Missense mutation, Coding region, Genetic Predisposition to Disease, Amino Acid Sequence, Cells, Cultured, Neurons, General Neuroscience, Lim Kinases, Hominidae, medicine.disease, Rats, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030217 neurology & neurosurgery
Abstract

International audience; LIMK2 is involved in neuronal functions by regulating actin dynamics. Different isoforms of LIMK2 are described in databanks. LIMK2a and LIMK2b are the most characterized. A few pieces of evidence suggest that LIMK2 isoforms might not have overlapping functions. In this study, we focused our attention on a less studied human LIMK2 isoform, LIMK2-1. Compared to the other LIMK2 isoforms, LIMK2-1 contains a supplementary C-terminal phosphatase 1 inhibitory domain (PP1i). We found out that this isoform was hominidae-specific and showed that it was expressed in human fetal brain and faintly in adult brain. Its coding sequence was sequenced in 173 patients with sporadic non-syndromic intellectual disability (ID), and we observed an association of a rare missense variant in the PP1i domain (rs151191437, p.S668P) with ID. Our results also suggest an implication of LIMK2-1 in neurite outgrowth and neurons arborization which appears to be affected by the p.S668P variation. Therefore our results suggest that LIMK2-1 plays a role in the developing brain, and that a rare variation of this isoform is a susceptibility factor in ID.

Published
2019

6. Effect of familial clustering in the genetic screening of 235 French ALS families

Author

Vincent Meininger, Sylviane Marouillat, François Salachas, Nathalie Guy, Emilien Bernard, Pierre-François Pradat, Annie Verschueren, Patrick Vourc'h, Stéphane Beltran, Pascal Cintas, Christian R. Andres, Débora Lanznaster, William Camu, Rudolph Hergesheimer, Céline Brulard, Sophie Pittion-Vouyovitch, Gwendal Le Masson, Frédéric Laumonnier, Philippe Couratier, Jean-Philippe Camdessanché, Marie-Céline Fleury, Philippe Corcia, Julien Cassereau, Marie-Hélène Soriani, Claude Desnuelle, Fausto Viader, Veronique Danel, Ivan Kolev, Hélène Blasco, Service de Neurologie, CHU Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), UMR U 1253, Université de Montpellier (UM), Service de Neurologie [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHRU de l'Hôpital de Bellevue, Services de Neurologie [CHU Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], centre de références des maladies neuromusculaires, Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Centre de compétence de la Sclérose Latérale Amyotrophique [CHU Clermont-Ferrand] (SLA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Neurologie, Département de Neurologie, CHU d’Angers, Angers, France, Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Département de Pharmacologie Médicale [Lille] (Pôle Recherche), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Unite de Neurophysiologie Clinique, Hopital Yves Le Foll, Saint-Brieuc, Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Francois Rabelais [Tours], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Hopital universitaire de Lyon, Hôpital Universitaire de Lyon, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Nucléaire [Tours], CHU Trousseau [APHP], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, and Grelier, Elisabeth

Subjects
Proband, Male, Genotype, DNA Mutational Analysis, Pedigree chart, Biology, TARDBP, 03 medical and health sciences, 0302 clinical medicine, Superoxide Dismutase-1, C9orf72, medicine, Cluster Analysis, Humans, Genetic Testing, Amyotrophic lateral sclerosis, 030304 developmental biology, Aged, Genetics, 0303 health sciences, C9orf72 Protein, Amyotrophic Lateral Sclerosis, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, Pedigree, DNA-Binding Proteins, Psychiatry and Mental health, Phenotype, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Mutation (genetic algorithm), Mutation, RNA-Binding Protein FUS, Surgery, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Age of onset, 030217 neurology & neurosurgery
Abstract

ObjectivesTo determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.MethodsWe conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.ResultsRegarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.ConclusionOur results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

Published
2021

7. Genes containing hexanucleotide repeats resembling C9ORF72 and expressed in the central nervous system are frequent in the human genome

Author

Patrick Vourc'h, Céline Brulard, Sandra Kassem, Kevin Mouzat, Audrey Dangoumau, Christian R. Andres, François Wurmser, Frédéric Laumonnier, Hélène Blasco, Philippe Corcia, Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)

Subjects
0301 basic medicine, Central Nervous System, Aging, [SDV]Life Sciences [q-bio], Central nervous system, Gene Expression, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, C9orf72, medicine, Humans, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Genetics, DNA Repeat Expansion, C9orf72 Protein, Genome, Human, General Neuroscience, Amyotrophic Lateral Sclerosis, Intron, C9orf72 Gene, Neurodegenerative Diseases, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Frontotemporal Dementia, Human genome, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology
Abstract

More than 40 human diseases, mainly diseases affecting the central nervous system, are caused by the expansion of unstable nucleotide repeats. Repeats of sequences like (CAG)n present in different genes can be responsible for various diseases of the central nervous system. An expanded hexanucleotide repeat (GGGGCC)n in the C9ORF72 gene has been characterized as the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar dementia. In this study, we performed a genome-wide analysis in the human genome and identified 74 genes containing this precise hexanucleotide repeat, with a preference for a location in exon 1 or intron 1, similar to the C9ORF72 gene. A total of 36 of these 74 genes may be of interest as candidates in neurodevelopmental or neurodegenerative diseases, based on their function.

Published
2021

8. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Julien Van-Gils, Kyoko Takano, Victor P. Pedro, Lauren Brick, Pascale Saugier-Veber, Tugce B. Balci, Antonio Vitobello, Marielle Alders, Justine Rousseau, Frédéric Laumonnier, Christel Thauvin-Robinet, Raoul C.M. Hennekam, Tjitske Kleefstra, Matt Tedder, Jennifer Kerkhof, Damien Sanlaville, Gaël Nicolas, François Lecoquierre, Delphine Héron, Hanxin Lin, Sophie Rondeau, Mariya Kozenko, Simone Pizzi, Alexandra Afenjar, Victoria Mok Siu, Christèle Dubourg, David Geneviève, Erfan Aref-Eshghi, Solveig Heide, Barbara R. DuPont, Peter Ainsworth, David I. Rodenhiser, Boris Keren, Nicole de Leeuw, Sandra Whalen, Martine Raynaud, Damien Ulveling, Nathalie Ruiz-Pallares, Valérie Cormier-Daire, Mouna Barat-Houari, Michael A. Levy, Roger E. Stevenson, Jennifer A. Lee, Steven A. Skinner, Alan Graham Stuart, Laurence Faivre, Marie Shaw, Gaetan Lesca, Peter Henneman, Thierry Bienvenu, Marco Tartaglia, Charles E. Schwartz, Andrea Ciolfi, Michael J. Friez, Michael Field, Mike Kadour, Guillaume Velasco, Jozef Gecz, Claire Francastel, Didier Lacombe, Philippe M. Campeau, Jean-Christophe Andrau, Bekim Sadikovic, Marcel M.A.M. Mannens, Jennifer Masters, Cyril Mignot, Patricia Fergelot, Nicolas Chatron, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, General Paediatrics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Quality of Care, London Health Sciences Center (LHSC), Schulich School of Medicine and Dentistry, University of Western Ontario (UWO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), 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, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Medical Center [Amsterdam], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan], IRCCS San Raffaele Scientific Institute [Milan, Italie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Sainte Justine [Montréal], McMaster University [Hamilton, Ontario], University of Tasmania [Hobart, Australia] (UTAS), Shinshu University Hospital, Radboud University Medical Center [Nijmegen], Hunter Genetics, University of Notre Dame [Indiana] (UND), University of South Australia [Adelaide], The Greenwood Genetic Center, Greenwood Genetic Center [Greenwood, South Carolina, USA], 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), Amsterdam Reproduction and Development Institute, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre épigénétique et destin cellulaire (EDC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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 National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Computational biology, 030105 genetics & heredity, Biology, Pediatrics, Article, Cohort Studies, molecular diagnostics, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, Gene duplication, Genetics, Humans, Hunter-McAlpine syndrome, Genetics (clinical), Mass screening, 030304 developmental biology, EpiSign, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA methylation, Genetic heterogeneity, 030305 genetics & heredity, Correction, Syndrome, DNA Methylation, Molecular diagnostics, Phenotype, Penetrance, Human genetics, 3. Good health, episignature, genomic DNA, 030104 developmental biology, Neurodevelopmental Disorders, uncertain clinical cases, Mendelian inheritance, symbols, Identification (biology), VUS classification
Abstract

Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access) Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Published
2020

9. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author

Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), 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), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), 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, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric

Subjects
0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online

Published
2020

10. Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability

Author

Anne Boland, Benjamin Cogné, Annick Toutain, Frédéric Laumonnier, Jean-François Deleuze, Marie-Laure Vuillaume, Stéphane Bézieau, Médéric Jeanne, D. Quinquis, Richard Redon, Dévina C. Ung, and Thomas Besnard

Subjects
Adult, 0301 basic medicine, Autism Spectrum Disorder, Clinical Biochemistry, 030105 genetics & heredity, Biology, Biochemistry, 03 medical and health sciences, Seizures, Intellectual Disability, medicine, Humans, RNA, Messenger, Gene, Chromosomal inversion, Genetics, Whole genome sequencing, Language Disorders, Whole Genome Sequencing, Biochemistry (medical), Chromosome, Forkhead Transcription Factors, General Medicine, FOXP1, medicine.disease, Phenotype, Repressor Proteins, 030104 developmental biology, Autism spectrum disorder, Mutation, Female, Haploinsufficiency
Abstract

The FOXP1 gene, located on chromosome 3p13, encodes the Forkhead-box protein P1, one of the four forkhead transcription factors which repress transcription by forming active homo- and heterodimers and regulate distinct patterns of gene expression crucial for embryogenesis and normal development. FOXP1 mutations, mostly truncating, have been described in patients with mild to moderate intellectual disability (ID), autism spectrum disorder (ASD), and speech and language impairment (MIM #613670). Here, we report a small de novo heterozygous balanced inversion of 2.1 Mb located at 3p14.1p13 identified by Whole Genomic Sequencing (WGS) and disrupting the genes FAM19A4 and FOXP1. This inversion was found in a patient with severe ID, ASD, seizures and very unusual vascular anomalies which were never described in the clinical spectrum of FOXP1 mutations. We show that the neurodevelopmental phenotype observed in the patient most likely results from FOXP1 haploinsufficiency as this heterozygous inversion leads to a 60 to 85% decrease of FOXP1 mRNA levels and to the complete absence of FOXP1 full-length protein. These findings, in addition to expanding the molecular spectrum of FOXP1 mutations, emphasize the emerging role of WGS in identifying small balanced chromosomal rearrangements responsible for neurodevelopmental disorders and not detected by conventional cytogenetics.

Published
2018

11. A novel mutation in the transmembrane 6 domain of GABBR2 leads to a Rett-like phenotype

Author

Céline Brulard, Philippe Parent, Stéphane Bézieau, Anne-Sophie Denommé-Pichon, Médéric Jeanne, Annick Toutain, Frédéric Laumonnier, Estelle Colin, Bertrand Isidor, Brigitte Gilbert-Dussardier, Audrey Donnart, Sylvie Odent, Sophie Blesson, Li Xue, Richard Redon, Servane Alirol, Philippe Rondard, and Marie-Laure Vuillaume

Subjects
0301 basic medicine, Genetics, Biology, medicine.disease, Phenotype, In vitro, Transmembrane protein, 03 medical and health sciences, Epileptic spasms, 030104 developmental biology, 0302 clinical medicine, Neurology, In vivo, medicine, Neurology (clinical), GABBR2, Functional studies, Novel mutation, 030217 neurology & neurosurgery
Abstract

We read with great interest the recent article published by Yooet al1reporting 4 additional Rett-like (RTT) patients with therecurring A567TGABBR2mutation.2More interestingly, theyshowed, with in vitro and in vivo functional studies, that theseverity of the phenotype caused byGABBR2mutations wasdirectly linked to their impact onc-aminobutyric acid (GABA)signaling activity, this latter being more reduced with the 2 mis-sense mutations, S695I and I705N, associated with epilepticencephalopathy (EE).1,3They hypothesized that the position ofvariants in different transmembrane (TM) domains ofGABBR2,TM6 for S695I and I705N, and TM3 for A567T, could deter-mine the phenotypic expression. This hypothesis was recentlyreinforced with the report of a novelGABBR2mutation also inTM6 and associated with infantile epileptic spasms.

Published
2018

12. Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment

Author

Jamel Chelly, George McGillivray, Jérémie Courraud, Katherine Rose, Amélie Piton, Marie‐Armel Savidan, Hélène Jagline, Angélique Quartier, Marie Shaw, Nathalie Drouot, Bertrand Isidor, Thuong Ha, Claire Feger, Frédéric Laumonnier, Jozef Gecz, and Jean-Louis Mandel

Subjects
Male, Models, Molecular, Autism Spectrum Disorder, Protein Conformation, Cell Adhesion Molecules, Neuronal, Population, Mutation, Missense, Nerve Tissue Proteins, Biology, medicine.disease_cause, 03 medical and health sciences, Neurodevelopmental disorder, X Chromosome Inactivation, Genetics, medicine, Missense mutation, Humans, Cognitive Dysfunction, Genetic Predisposition to Disease, education, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, education.field_of_study, Mutation, Endoplasmic reticulum, 030305 genetics & heredity, HEK 293 cells, Membrane Proteins, medicine.disease, Pedigree, Protein Transport, Phenotype, Autism spectrum disorder, Unfolded protein response, Female
Abstract

The X-linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a nonsyndromic monogenic form of autism spectrum disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD: c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an unfolded protein response, probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD.

Published
2019

13. Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism

Author

Patrick Vourc'h, Annick Toutain, Catherine Barthélémy, Joëlle Malvy, Loïc Decalonne, Hélène Bénédetti, Rose-Anne Thépault, Frédéric Laumonnier, Refaat Tabagh, Sylviane Marouillat, Frédérique Bonnet-Brilhault, Agathe Paubel, Christian R. Andres, Julie Tastet, University Medical Center [Utrecht], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), INSERM 930, CHU Bretonneau, Université Francois Rabelais [Tours], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau

Subjects
Adult, Male, Adolescent, [SDV]Life Sciences [q-bio], Ubiquitin-Protein Ligases, Mutation, Missense, Bioinformatics, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, Genotype, Genetics, medicine, Humans, Missense mutation, Coding region, RNA, Messenger, Autistic Disorder, Allele, Child, Gene, Biological Psychiatry, Genetics (clinical), 030304 developmental biology, 0303 health sciences, biology, Middle Aged, medicine.disease, 3. Good health, Ubiquitin ligase, Psychiatry and Mental health, Case-Control Studies, Child, Preschool, biology.protein, Autism, Female, France, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

International audience; Many genes are now thought to confer susceptibility to autism. Despite the fact that this neuropsychiatric disease appears to be related to several different causes, common cellular and molecular pathways have emerged and point to synaptic dysfunction or cellular growth. Several studies have indicated the importance of the ubiquitin pathway in synaptic function and the aetiology of autism. Here, we focused on the ring finger protein 135 (RNF135) gene, encoding an E3 ubiquitin ligase expressed in the cortex and cerebellum, and located in the NF1 gene locus in 17q11.2, a region linked to autism. We carried out a genetic analysis of the coding sequence of RFN135 in a French cohort of patients with autism and observed a significantly increased frequency of genotypes carrying the rare allele of the rs111902263 (p.R115K) missense variant in patients (P=0.0019, odds ratio : 4.23, 95% confidence interval : 1.87-9.57). Particularly, three unrelated patients showed a homozygous genotype for K115, a situation not observed in the 1812 control individuals. Further cellular and molecular studies are required to elucidate the role of this gene and the variant K115 in brain development and neuronal function.

Published
2015

14. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation

Author

Michael Partington, Jozef Gecz, Irma Järvelä, Michael Field, Michael R. Stratton, Lucianne Vandeleur, Jamel Chelly, Karen Govaerts, Cliff Meldrum, Hans van Bokhoven, Patrick S. Tarpey, P. Andrew Futreal, F. Lucy Raymond, Hilde Van Esch, Maarit Peippo, Peter Marynen, Fatima Abidi, Marijke Bauters, Damien Sanlaville, Annabel Whibley, David Mowat, Guido Froyen, Anna Hackett, Rodney J. Scott, Owen Lawrence, Gillian Turner, Frédéric Laumonnier, Marjatta Sipponen, Mark A. Corbett, Joke Vandewalle, Jean-Pierre Fryns, Charles E. Schwartz, Hans-Hilger Ropers, Enzo Ranieri, and University of Groningen

Subjects
Genetics and epigenetic pathways of disease [NCMLS 6], DNA Mutational Analysis, Gene Dosage, PROTEIN, HSD17B10, 0302 clinical medicine, Gene Duplication, Gene duplication, Genetics(clinical), COMPARATIVE GENOMIC HYBRIDIZATION, Genetics (clinical), In Situ Hybridization, Fluorescence, GENE-EXPRESSION, Genetics, 0303 health sciences, ISOLEUCINE, ABNORMALITIES, 3-Hydroxyacyl CoA Dehydrogenases, Phenotype, 3. Good health, Ubiquitin ligase, Pedigree, DEFICIENCY, Functional Neurogenomics [DCN 2], DNA, Complementary, Ubiquitin-Protein Ligases, Blotting, Western, Molecular Sequence Data, Biology, ANGELMAN SYNDROME, Gene dosage, X-inactivation, Article, 03 medical and health sciences, Cognitive neurosciences [UMCN 3.2], Humans, Gene, 030304 developmental biology, Chromosomes, Human, X, Base Sequence, MUTATIONS, Point mutation, Tumor Suppressor Proteins, Microarray Analysis, Molecular biology, Mutation, BRAIN DISEASES, biology.protein, Mental Retardation, X-Linked, 030217 neurology & neurosurgery, ARRAY-CGH, Immunity, infection and tissue repair [NCMLS 1]
Abstract

Contains fulltext : 70916.pdf (Publisher’s version ) (Closed access) Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.

Published
2008

15. Disruption of TCA Cycle and Glutamate Metabolism Identified by Metabolomics in an In Vitro Model of Amyotrophic Lateral Sclerosis

Author

Lydie Nadal-Desbarats, Hélène Blasco, Patrick Vourc'h, Patrick Emond, Flore Gouel, Audrey Dangoumau, Frédéric Laumonnier, Charlotte Veyrat-Durebex, Christian R. Andres, David Devos, Eric Piver, Philippe Corcia, and Paul H. Gordon

Subjects
0301 basic medicine, Quality Control, Time Factors, Cell Survival, SOD1, Citric Acid Cycle, Green Fluorescent Proteins, Neuroscience (miscellaneous), Biology, medicine.disease_cause, Models, Biological, Gas Chromatography-Mass Spectrometry, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Metabolomics, Glutamates, medicine, Humans, Amyotrophic lateral sclerosis, Principal Component Analysis, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Discriminant Analysis, Reproducibility of Results, Vitamin K 3, medicine.disease, Coculture Techniques, Citric acid cycle, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, Neurology, Biochemistry, Cellular model, Reactive Oxygen Species, 030217 neurology & neurosurgery, Intracellular, Oxidative stress, Astrocyte
Abstract

This study aims to develop a cellular metabolomics model that reproduces the pathophysiological conditions found in amyotrophic lateral sclerosis in order to improve knowledge of disease physiology. We used a co-culture model combining the motor neuron-like cell line NSC-34 and the astrocyte clone C8-D1A, with each over-expressing wild-type or G93C mutant human SOD1, to examine amyotrophic lateral sclerosis (ALS) physiology. We focused on the effects of mutant human SOD1 as well as oxidative stress induced by menadione on intracellular metabolism using a metabolomics approach through gas chromatography coupled with mass spectrometry (GC-MS) analysis. Preliminary non-supervised analysis by Principal Component Analysis (PCA) revealed that cell type, genetic environment, and time of culture influenced the metabolomics profiles. Supervised analysis using orthogonal partial least squares discriminant analysis (OPLS-DA) on data from intracellular metabolomics profiles of SOD1G93C co-cultures produced metabolites involved in glutamate metabolism and the tricarboxylic acid cycle (TCA) cycle. This study revealed the feasibility of using a metabolomics approach in a cellular model of ALS. We identified potential disruption of the TCA cycle and glutamate metabolism under oxidative stress, which is consistent with prior research in the disease. Analysis of metabolic alterations in an in vitro model is a novel approach to investigation of disease physiology.

Published
2015

16. GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability

Author

RA Thépault, Sylviane Marouillat, Annick Toutain, Bazaud S, Frédérique Bonnet-Brilhault, Romuald Blanc, Catherine Barthélémy, Martine Raynaud, Servane Alirol, Christian R. Andres, Lemonnier É, Frédéric Laumonnier, and Marie Gomot

Subjects
0301 basic medicine, Male, Cell Adhesion Molecules, Neuronal, Glutamic Acid, Genomics, Severity of Illness Index, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Intellectual Disability, Genetic model, Intellectual disability, medicine, Humans, Genetic Predisposition to Disease, ANK3, Autistic Disorder, Molecular Biology, gamma-Aminobutyric Acid, Family Health, Genetic heterogeneity, Electroencephalography, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Acoustic Stimulation, Schizophrenia, Child, Preschool, Behavioral medicine, Evoked Potentials, Auditory, Autism, Female, Psychology, Neuroscience, 030217 neurology & neurosurgery, Follow-Up Studies, Signal Transduction
Abstract

Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.

Published
2015

17. 1H-13C NMR-based urine metabolic profiling in autism spectrum disorders

Author

Catherine Barthélémy, Frédéric Montigny, Lydie Nadal-Desbarats, Frédérique Bonnet-Brilhault, Hélène Blasco, Patrick Vourc'h, Sylvie Mavel, Patrick Emond, Frédéric Laumonnier, Pierre Sarda, Christian R. Andres, Equipe neurogénétique et neurométabolomique, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-PPF 'Analyses des Systèmes Biologiques', Université de Tours-Université de Tours, Equipe Autisme, PPF 'Analyses des Systèmes Biologiques', Université de Tours, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), INSERM, University François-Rabelais, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PPF 'Analyses des Systèmes Biologiques', Université de Tours (UT)-Université de Tours (UT), Université de Tours (UT), and Mavel, Sylvie

Subjects
Male, medicine.medical_specialty, Adolescent, HSQC NMR spectroscopy, Urine, Creatine, Analytical Chemistry, Correlation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Nuclear magnetic resonance, Internal medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Urinary metabolites, Least-Squares Analysis, Child, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, 0303 health sciences, Principal Component Analysis, Carbon-13 NMR, Autism spectrum disorders, medicine.disease, OPLS-DA, 3. Good health, Endocrinology, chemistry, Child Development Disorders, Pervasive, Case-Control Studies, OPLS- DA, Metabolome, Autism, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, Two-dimensional nuclear magnetic resonance spectroscopy, 030217 neurology & neurosurgery, Heteronuclear single quantum coherence spectroscopy
Abstract

International audience; Autism Spectrum Disorders (ASD) are a group of developmental disorders caused by environmental and genetic factors. Diagnosis is based on behavioral and developmental signs detected before 3 years of age with no reliable biological marker. The purpose of this study was to evaluate the potential use of a 2D NMR-based approach to express the global biochemical signature of autistic individuals compared to normal controls. This technique has greater spectral resolution than to 1D (1)H NMR spectroscopy, which is limited by overlapping signals. The urinary metabolic profiles of 30 autistic and 28 matched healthy children were obtained using a (1)H-(13)C NMR-based approach. The data acquired were processed by multivariate orthogonal partial least-squares discriminant analysis (OPLS-DA). Some discriminating metabolites were identified: β-alanine, glycine, taurine and succinate concentrations were significatively higher, and creatine and 3-methylhistidine concentrations were lower in autistic children than in controls. We also noted differences in several other metabolites that were unidentified but characterized by a cross peak correlation in (1)H-(13)C HSQC. Statistical models of (1)H and (1)H-(13)C analyses were compared and only 2D spectra allowed the characterization of statistically relevant changes [R(2)Y(cum)=0.78 and Q(2)(cum)=0.60] in the low abundance metabolites. This method has the potential to contribute to the diagnosis of neurodevelopment disorders but needs to be validated on larger cohorts and on other developmental disorders to define its specificity.

Published
2013

18. GC-MS-based urine metabolic profiling of autism spectrum disorders

Author

Frédéric Montigny, Frédéric Laumonnier, Christian R. Andres, Catherine Barthélémy, Frédérique Bonnet-Brilhault, Patrick Vourc'h, Pierre Sarda, Hélène Blasco, Marc Merten, Nacima Aïdoud, Lydie Nadal-Desbarats, Patrick Emond, Sylvie Mavel, Equipe neurogénétique et neurométabolomique, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PPF 'Analyses des Systèmes Biologiques', Université de Tours (UT)-Université de Tours (UT), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), PPF 'Analyses des Systèmes Biologiques', Université de Tours (UT), Equipe Autisme, Laboratoire de Biochimie, Université Henri Poincaré - Nancy 1 (UHP), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and INSERM, University François-Rabelais

Subjects
Male, Multivariate analysis, Urine, Chemical Fractionation, 01 natural sciences, Biochemistry, MESH: Child Development Disorders, Pervasive, Analytical Chemistry, chemistry.chemical_compound, MESH: Child, MESH: Metabolomics, Child, GC, 0303 health sciences, Biomedical analysis, Chemistry, Statistics, MESH: Case-Control Studies, Multiple factors, Bioanalytical methods, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.medical_specialty, Adolescent, Gas Chromatography-Mass Spectrometry, 03 medical and health sciences, Clinical, MESH: Chemical Fractionation, Metabolomics, Internal medicine, medicine, Humans, Chemometrics, Derivatization, 030304 developmental biology, MESH: Adolescent, Chromatography, MESH: Humans, Mass spectrometry, 010401 analytical chemistry, Case-control study, medicine.disease, MESH: Male, 0104 chemical sciences, MESH: Gas Chromatography-Mass Spectrometry, Endocrinology, Child Development Disorders, Pervasive, Case-Control Studies, Autism, Gas chromatography–mass spectrometry, MESH: Female
Abstract

International audience; Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders resulting from multiple factors. Diagnosis is based on behavioural and developmental signs detected before 3 years of age, and there is no reliable biological marker. The purpose of this study was to evaluate the value of gas chromatography combined with mass spectroscopy (GC-MS) associated with multivariate statistical modeling to capture the global biochemical signature of autistic individuals. GC-MS urinary metabolic profiles of 26 autistic and 24 healthy children were obtained by liq/liq extraction, and were or were not subjected to an oximation step, and then were subjected to a persilylation step. These metabolic profiles were then processed by multivariate analysis, in particular orthogonal partial least-squares discriminant analysis (OPLS-DA, R(2)Y(cum) = 0.97, Q(2)(cum) = 0.88). Discriminating metabolites were identified. The relative concentrations of the succinate and glycolate were higher for autistic than healthy children, whereas those of hippurate, 3-hydroxyphenylacetate, vanillylhydracrylate, 3-hydroxyhippurate, 4-hydroxyphenyl-2-hydroxyacetate, 1H-indole-3-acetate, phosphate, palmitate, stearate, and 3-methyladipate were lower. Eight other metabolites, which were not identified but characterized by a retention time plus a quantifier and its qualifier ion masses, were found to differ between the two groups. Comparison of statistical models leads to the conclusion that the combination of data obtained from both derivatization techniques leads to the model best discriminating between autistic and healthy groups of children.

Published
2013

19. ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity

Author

Jill A. Rosenfeld, Frédéric Laumonnier, Dima El-Khechen, Elke Schellenberger, Wolfram Kress, Christoph Hübner, Peter Wieacker, Lam Son Nguyen, Thomas Haaf, Astrid Grimme, Gai L McMichael, Alastair H. MacLennan, Vera M. Kalscheuer, Hans-Hilger Ropers, Lisa G. Shaffer, Luis F. Escobar, Alison Gardner, Jamel Chelly, Sabine Preisler-Adams, Sylviane Marouillat, Marie Shaw, Hiromi Hirata, Werner Stenzel, Melanie Hambrock, Géraldine Viot, Indrajit Nanda, Ute Fischer, Dominik Seelow, Nicolas Lebrun, Markus Schuelke, Raoul C.M. Hennekam, Can Ding, M Bienek, Servane Alirol, Rena E. Falk, Eric Haan, Hao Hu, Richard Webster, Stefan A. Haas, Nancy Kramer, Marie-Amélie Papon, Tzu Ying Yap, Jozef Gecz, Anne van Riesen, Amsterdam Neuroscience, Amsterdam Public Health, Human Genetics, and Paediatrics

Subjects
Male, medicine.disease_cause, Chromosome Breakpoints, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Missense mutation, Genetics(clinical), Cells, Cultured, In Situ Hybridization, Zebrafish, Genetics (clinical), Arthrogryposis, Genetics, Comparative Genomic Hybridization, 0303 health sciences, Mutation, Neuronal Plasticity, medicine.diagnostic_test, Intracellular Signaling Peptides and Proteins, High-Throughput Nucleotide Sequencing, Nuclear Proteins, Zinc Fingers, Pedigree, 3. Good health, Female, medicine.symptom, Genetic counseling, Immunoblotting, Biology, Article, 03 medical and health sciences, Intellectual Disability, medicine, Animals, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, 030304 developmental biology, Genetic testing, Arthrogryposis multiplex congenita, Point mutation, medicine.disease, Haplotypes, Synapses, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired alpha-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.

Published
2013

20. FG syndrome: The FGS2 locus revisited

Author

Béatrice Laudier, Sylvain Briault, Frédéric Laumonnier, Olivier Perche, Arnaud Menuet, Sylvie Odent, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional d'Orléans (CHRO), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, FG syndrome, Locus (genetics), [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Anus, Imperforate, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Family, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Chromosomes, Human, X, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, 030305 genetics & heredity, Chromosome Mapping, medicine.disease, 3. Good health, Genetic Loci, Mutation, Mental Retardation, X-Linked, Muscle Hypotonia, Agenesis of Corpus Callosum, Constipation
Abstract

FG Syndrome: The FGS2 Locus Revisited Olivier Perche, B eatrice Laudier, Arnaud Menuet, Sylvie Odent, Frederic Laumonnier, and Sylvain Briault* Molecular and Experimental Immunology and Neurogenetics, UMR7355, University of orl eans, 3b Rue de la F erollerie, Orl eans La Source, Cedex 2, France Centre Hospitalier R egional d’Orl eans, Avenue de l’Hopital, Orl eans La Source, Cedex 1, France Centre hospitalier universitaire de Rennes, Hopital sud, Service de g en etique clinique 16, boulevard de Bulgarie, Rennes Cedex 2, France UMR « Imagerie et Cerveau », INSERM, U930 CNRS ERL3106, Francois-Rabelais University, Medical University, Tours Cedex, France

Published
2012

21. LIMK2d, a truncated isoform of Lim kinase 2 regulates neurite growth in absence of the LIM kinase domain

Author

Hélène Bénédetti, Anne Duittoz, Julie Tastet, Frédéric Laumonnier, Béatrice Vallée, Caroline Michelle, Patrick Vourc'h, Christian R. Andres, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Region Centre, la Ligue contre le Cancer, CNRS, Université François Rabelais de Tours, Ministère de l'Enseignement Supérieur et de la Recherche, Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
Gene isoform, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], neurite outgrowth, Neurite, Biophysics, macromolecular substances, Biology, Biochemistry, Hippocampus, Lim kinase, 03 medical and health sciences, Mice, 0302 clinical medicine, Cerebellum, Neurites, Animals, Molecular Biology, Protein kinase C, Actin, Cells, Cultured, 030304 developmental biology, limk2, 0303 health sciences, Lim Kinases, Cell Biology, Cofilin, Actin cytoskeleton, Molecular biology, Actins, Cell biology, Protein Structure, Tertiary, Rats, Isoenzymes, Protein kinase domain, nervous system, altrnative splicing, 030217 neurology & neurosurgery
Abstract

Lim kinase 2 isoforms, LIMK2a and LIMK2b, phosphorylate cofilin leading to remodeling of actin cytoskeleton during neuronal differentiation. The expression and function of the LIMK2d isoform, missing the kinase domain, remain unknown. We analyzed the expression of LIMK2 splice variants in adult rat brain and in cultures of rat neural stem cells by RT-QPCR. All three splice variants were expressed in adult cortex, hippocampus and cerebellum. Limk2a and Limk2d expression, but not Limk2b, increased during neuronal differentiation. We studied the localization and function of LIMK2d isoform by transfecting Hela, NSC-34, and hippocampal rat neuron cultures. Similarly to LIMK2b, LIMK2d was expressed in the cytoplasm, neurites and dendritic spines, but not in the nucleus. Similarly to LIMK2a, LIMK2d over-expression in NSC-34 cells increased neurite length, but independently of cofilin phosphorylation or of direct interaction with actin. Overall, these results indicate that LIMK2d is a third LIMK2 isoform which regulates neurite extension and highlights the possible existence of a kinase independent function of LIMK2.

Published
2012

22. Autisme, génétique et anomalies de la fonction synaptique

Author

Sylvain Briault, Stéphane Mortaud, Frédéric Laumonnier, Céline Montécot-Dubourg, Olivier Richard, Maryvonne Ardourel, V. Robin, Arnaud Menuet, Olivier Perche, Lekbir Baala, Jacques Pichon, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre Hospitalier Régional d'Orléans (CHRO), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), laboratoire de Neurobiologie, Université d'Orléans (UO), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], Disease, Biology, behavioral disciplines and activities, 03 medical and health sciences, symbols.namesake, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, mental disorders, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, General Medicine, medicine.disease, Comorbidity, 3. Good health, Developmental disorder, Asperger syndrome, Mendelian inheritance, symbols, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery
Abstract

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

Published
2010

23. Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with Intellectual Disability

Author

Richard Delorme, Didier Lacombe, Cécile Pagan, Frédéric Laumonnier, Marion Leboyer, Anne Dumaine, Jamel Chelly, Marjolein H. Willemsen, Karine Poirier, Martine Raynaud, Arjan P.M. de Brouwer, Stéphane Jamain, Sylvain Briault, Hany Goubran Botros, Andreas Tzschach, Vera M. Kalscheuer, Hilde Van Esch, Sarah Moreno, Jean-Marie Launay, Bregje W.M. van Bon, Thomas Bourgeron, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), 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), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Foundation Fondamental, Department of Human Genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences, Center for Human Genetics, University Hospitals Leuven [Leuven], Récepteurs et Cognition (RC), Collège de France (CdF (institution))-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department Human Molecular Genetics [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, Centre Hospitalier Régional Universitaire, Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Henri Mondor-Albert Chenevier Group, This work was supported by the Pasteur Institute, INSERM, Assistance Publique des Hôpitaux de Paris, and the RTRS Santé Mentale (Foundation FondaMental)., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Collège de France (CdF (institution))-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), BMC, Ed., Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), 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 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Récepteurs et Cognition ( RC ), Collège de France ( CdF ) -Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Max Planck Institute for Molecular Genetics ( MPIMG ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Immunologie et embryologie moléculaires ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Henri Mondor-Albert Chenevier Group

Subjects
MESH: Sequence Analysis, DNA, Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3], [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Exon, 0302 clinical medicine, MESH: Mental Retardation, Genetics(clinical), [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), MESH: Melatonin, MESH: Sleep Disorders, Melatonin, Genetics, MESH: Acetylserotonin O-Methyltransferase, 0303 health sciences, Mutation, MESH : Melatonin, medicine.diagnostic_test, MESH: Genetic Testing, Effective primary care and public health [NCEBP 7], MESH: Case-Control Studies, MESH : Acetylserotonin O-Methyltransferase, MESH : Mutation, Metabolic Networks and Pathways, medicine.drug, Research Article, Acetylserotonin O-Methyltransferase, Sleep Wake Disorders, MESH : Case-Control Studies, medicine.medical_specialty, lcsh:Internal medicine, MESH: Mutation, lcsh:QH426-470, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, MESH : Genetic Testing, Internal medicine, Intellectual Disability, medicine, Humans, MESH : Mental Retardation, Genetic Testing, lcsh:RC31-1245, Gene, 030304 developmental biology, Genetic testing, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Humans, Case-control study, MESH : Metabolic Networks and Pathways, Sequence Analysis, DNA, Human genetics, lcsh:Genetics, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Acetylserotonin O-methyltransferase, MESH: Metabolic Networks and Pathways, MESH : Sleep Disorders, Case-Control Studies, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, MESH : Sequence Analysis, DNA
Abstract

Background Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls. Methods Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls. Results We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004). Conclusions We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis.

Published
2011

24. Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

Author

Frédéric Laumonnier, Tjitske Kleefstra, Hao Hu, Nael Nadif Kasri, Lisenka E.L.M. Vissers, Willemijn M. Wissink-Lindhout, Thomas F. Wienker, Hanka Venselaar, Sylviane Marouillat, Marco Benevento, Arjan P.M. de Brouwer, Anneke T. Vulto-van Silfhout, Marie-Amélie Papon, Kimia Kahrizi, Hans van Bokhoven, Marjolein H. Willemsen, Luciana Musante, Hans-Hilger Ropers, Zafar Iqbal, and Hossein Najmabadi

Subjects
Male, Dendritic spine, Amino Acid Transport Systems, medicine.disease_cause, Hippocampus, Plasma Membrane Neurotransmitter Transport Proteins, Mice, 0302 clinical medicine, Intellectual disability, Tremor, Genetics(clinical), Exome, Genetics (clinical), Exome sequencing, Genetics, 0303 health sciences, Mutation, Mental Disorders, Homozygote, Glutamate receptor, Chromosome Mapping, Middle Aged, Disease gene identification, 3. Good health, Pedigree, Phenotype, Female, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], DNA Copy Number Variations, Molecular Sequence Data, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Biology, Transfection, Speech Disorders, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Glutamatergic, Young Adult, Intellectual Disability, medicine, Animals, Humans, Amino Acid Sequence, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, Mice, Inbred C57BL, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

Contains fulltext : 152998.pdf (Publisher’s version ) (Closed access) We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses.

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25. Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

Author

Solenn Legallic, Audrey Guilmatre, Gael Le Vacon, Catherine Barthélémy, Claude Bendavid, Thierry Frebourg, Christian R. Andres, Eva Germanò, Véronique David, Laurence Faivre, Frédéric Laumonnier, Sylvain Briault, Christèle Dubourg, Antoine Rosier, Gaetano Tortorella, Valérie Drouin-Garraud, Pascale Saugier Veber, Alice Goldenberg, Dominique Campion, Géraldine Joly-Helas, Jean-Michel Pinoit, Valérie Layet, A.L. Mosca, Gabriella Di Rosa, Sylvie Odent, Frédérique Bonnet-Brilhault, C. Henry, Caterina Impallomeni, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Centre de Ressources Autisme de Haute Normandie (CRAHN), Centre de Ressources Autisme de Haute Normandie, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier spécialisé du Rouvray, Centre Ressources Autisme de Bourgogne (CHU de Dijon) (CRAB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Medical and Surgical Pediatrics, University Hospital, Messina, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), AG received a fellowship from Region Haute Normandie and ALM from the Académie Nationale de Médecine. We acknowledge the financial support of the Fondation de France. We acknowledge the support of the collaborative biological resource from the autism foundation (RBCFA) and of the Autism foundation. We acknowledge the technical support of the transcriptomic platform of the OUEST Genopole® (Rennes) and of the Genethon., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique, hôpital Sud, De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Gene Dosage, [SDV.GEN] Life Sciences [q-bio]/Genetics, copy number variations, mental retardation, autism, MESH: Gene Dosage, MESH: Genotype, 0302 clinical medicine, Gene Frequency, MESH: Mental Retardation, Copy-number variation, MESH: In Situ Hybridization, Fluorescence, [SDV.BDD]Life Sciences [q-bio]/Development Biology, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Comparative Genomic Hybridization, Chromosome Mapping, MESH: Case-Control Studies, 3. Good health, Psychiatry and Mental health, Schizophrenia, Autism spectrum disorder, Female, Psychology, Adult, Psychosis, Adolescent, Genotype, Proline, Neurogenesis, MESH: Autistic Disorder, Context (language use), Schizoaffective disorder, MESH: Psychotic Disorders, Article, 03 medical and health sciences, Arts and Humanities (miscellaneous), Intellectual Disability, [SDV.BDD] Life Sciences [q-bio]/Development Biology, mental disorders, medicine, MESH: Gene Frequency, Humans, Autistic Disorder, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Proline, MESH: Adult, medicine.disease, MESH: Male, MESH: Schizophrenia, MESH: Neurogenesis, Developmental disorder, MESH: Comparative Genomic Hybridization, Psychotic Disorders, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Case-Control Studies, MESH: Oligonucleotide Array Sequence Analysis, Autism, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; CONTEXT: Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. OBJECTIVES: To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. MAIN OUTCOME MEASURES: Collective and individual frequencies of the analyzed CNVs in cases compared with controls. RESULTS: Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. CONCLUSIONS: Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

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