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1. Copy-Number Variants in The Contactin-5 Gene Are a Potential Risk Factor for Autism Spectrum Disorder

Author

Elise Douard, Herve Lemaitre, Amélie Musa-Johnson, Lan Xiong, Guy A. Rouleau, Caroline Hayward, Gunter Schumann, Tobias Banaschewski, Boris Chaumette, Sylvane Desrivières, Mor Absa Loum, Guillaume Huguet, Arun L.W. Bokde, Patrick A. Dion, Calwing Liao, Alexandre Dionne-Laporte, Zoe Schmilovich, Qin He, Jay P. Ross, Dan Spiegelman, Sébastien Jacquemont, Martinez Rico, Clara, McGill University = Université McGill [Montréal, Canada], CHU Sainte Justine [Montréal], Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), University of Edinburgh, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim], Trinity College Dublin, King‘s College London, Université Paris-Saclay, Montreal Neurological Institute and Hospital, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
Genetics, genetic structures, neurodevelopment, Potential risk, business.industry, CNTN5, Contactin 5, intronic deletions, CNV, Biology, medicine.disease, behavioral disciplines and activities, ASD, inherited, Text mining, Autism spectrum disorder, mental disorders, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Copy-number variation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Gene
Abstract

BackgroundContactin-5 (CNTN5) is a candidate risk gene for autism spectrum disorder (ASD), yet previous attempts to associate copy-number variants (CNVs) encompassing CNTN5 with ASD-susceptibility were limited by insufficient statistical power. Here, we aim to clarify the putative association between CNTN5 CNVs and ASD-risk using large samples. MethodsFirst, we calculated the prevalence and transmission of CNTN5 CNVs in ASD across three ASD cohorts (SSC, MSSNG, and SPARK), the cases reported in the Mercati et al. study, and the BBGRE database (n = 16,607). Second, we modelled their transmission in children with ASD compared to their unaffected siblings. Third, we assessed their frequency in cases with ASD compared to unselected population controls (n = 24,898) and replicated the findings in UK Biobank (UKBB), an independent general population cohort (n = 459,855). Finally, we evaluated the clinical impact of CNTN5 CNVs by assessing their enrichment in a broad neurodevelopmental disorder (NDD) cohort, and the clinical profile of CNTN5 CNV carriers in the DECIPHER database.ResultsThe prevalence of CNTN5 exonic deletions and duplications was stable across ASD and across unselected cohorts (0.042% and 0.020%, respectively). We found a significant enrichment of intronic CNTN5 deletions CNVs in ASD compared to unselected controls (0.175% and 0.004%, respectively). CNVs in most cases with ASD (29 out of 30, 96.7%) were inherited. Parents transmitted the variants to their affected and unaffected children with the same frequency. No differences in exonic CNTN5 CNVs enrichment between cases with ASD compared to individuals with NDDs was observed. LimitationsThe lack of phenotypic data available for unaffected family members of probands with ASD limits the potential to assess whether CNTN5 CNVs segregate with other neuropsychiatric or sub-threshold autistic traits. Different genotyping or sequencing technologies may affect the differences in CNTN5 CNV prevalence across cohorts.ConclusionCNTN5 CNVs are rare inherited ASD susceptibility variants. They may also confer risk for other neuropsychiatric disorders. We offer a powerful framework to investigate candidate susceptibility variants that may not be detected through small-scale approaches. This approach may reveal more intermediate effect-size variants that are implicated in the etiology of ASD.

Published
2021

2. A polymorphism in the glutamate metabotropic receptor 7 is associated with cognitive deficits in the early phases of psychosis

Author

Oussama Kebir, Marie-Odile Krebs, Sarojini M. Sengupta, Martin Lepage, Ridha Joober, Srividya N. Iyer, Boris Chaumette, Jai Shah, Guy A. Rouleau, Patrick A. Dion, Ashok Malla, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), GHU Paris Psychiatrie et Neurosciences, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Department of Psychiatry [Montréal], Groupement de recherche en Psychiatrie (GDR Psychiatrie (3557)), Centre National de la Recherche Scientifique (CNRS), Douglas Mental Health University Institute [Montréal], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Martinez Rico, Clara

Subjects
Psychosis, Premorbid, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Single-nucleotide polymorphism, Neuropsychological Tests, Receptors, Metabotropic Glutamate, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, Glutamatergic, [SCCO]Cognitive science, Cognition, 0302 clinical medicine, Glutamates, medicine, Genetics, Humans, Cognitive Dysfunction, Biological Psychiatry, Genetic association, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Wechsler Adult Intelligence Scale, [SCCO] Cognitive science, medicine.disease, 030227 psychiatry, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, IQ, Prodromal, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cohort, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway.

Published
2020

3. Oligogenicity, C9orf72 expansion, and variant severity in ALS

Author

Patrick A. Dion, William Camu, Claire S. Leblond, Guy A. Rouleau, Nicolas Dupré, Alexandre Dionne-Laporte, Dan Spiegelman, Sandra B. Laurent, Jay P. Ross, McGill University = Université McGill [Montréal, Canada], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Faculté de médecine de l'Université Laval [Québec] (ULaval), Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], and Jay Ross has received a doctoral student fellowship from the ALS Society of Canada and a Canadian Institutes of Health Research Frederick Banting & Charles Best Canada Graduate Scholarship (FRN 159279). We thank the ALS Society of Canada, the Canadian Institutes of Health Research, and Brain Canada for research funding.

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, MESH: Sequence Analysis, DNA, MESH: DNA Repeat Expansion, Pathogenesis, Cohort Studies, C9orf72 expansion, 0302 clinical medicine, C9orf72, MESH: Genetic Variation, Amyotrophic lateral sclerosis, MESH: Cohort Studies, Genetics (clinical), MESH: Amyotrophic Lateral Sclerosis, Genetics, MESH: Aged, DNA Repeat Expansion, MESH: Middle Aged, Variant severity, Oligogenic Inheritance, Middle Aged, Frontotemporal Dementia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, MESH: C9orf72 Protein, Adult, Canada, MESH: Frontotemporal Dementia, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Canada, medicine, Humans, Gene, Aged, MESH: Humans, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Genetic Variation, MESH: Adult, Sequence Analysis, DNA, medicine.disease, Molecular medicine, Human genetics, MESH: Male, Oligogenicity, MESH: France, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Disease Presentation, ALS, MESH: Multifactorial Inheritance, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; "Oligogenic inheritance" is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.

Published
2020

4. SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease

Author

Roy N, Alcalay, Victoria, Mallett, Benoît, Vanderperre, Omid, Tavassoly, Yves, Dauvilliers, Richard Y J, Wu, Jennifer A, Ruskey, Claire S, Leblond, Amirthagowri, Ambalavanan, Sandra B, Laurent, Dan, Spiegelman, Alexandre, Dionne-Laporte, Christopher, Liong, Oren A, Levy, Stanley, Fahn, Cheryl, Waters, Sheng-Han, Kuo, Wendy K, Chung, Blair, Ford, Karen S, Marder, Un Jung, Kang, Sharon, Hassin-Baer, Lior, Greenbaum, Jean-Francois, Trempe, Pavlina, Wolf, Petra, Oliva, Xiaokui Kate, Zhang, Lorraine N, Clark, Melanie, Langlois, Patrick A, Dion, Edward A, Fon, Nicolas, Dupre, Guy A, Rouleau, Ziv, Gan-Or, Columbia University Medical Center (CUMC), Columbia University [New York], McGill University = Université McGill [Montréal, Canada], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Montreal Neurological Institute and Hospital, Université Laval [Québec] (ULaval), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Nowak, Cécile

Subjects
Male, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Parkinson's disease, Brain, Parkinson Disease, Middle Aged, Article, Sphingomyelin Phosphodiesterase, α-synuclein, Gene Knockdown Techniques, Jews, Mutation, alpha-Synuclein, Humans, Female, Genetic Predisposition to Disease, SMPD1, genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], acid sphingomyelinase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged, HeLa Cells
Abstract

International audience; Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

5. RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement

Author

Patrick A. Dion, Alex Parker, Aida Abu-Baker, Masoud Shekarabi, Guy A. Rouleau, Nawwaf Kharma, Claudia Maios, Michele Dona, Christian Neri, Alanna Grant, Luc Varin, Jonathan Perreault, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Electrical and Computer Engineering Department [Concordia] (ECE), Concordia University [Montreal], Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Université de Montréal (UdeM), Centre Hospitalier de l'Université de Montréal (CHUM), Université Paris Descartes - Paris 5 (UPD5), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Canadian Institutes of Health Research (CIHR) operating grant: Characterization of PABPN1 for the development of an OPMD treatment (JNM-85075), Muscular Dystrophy Canada, the Muscular Dystrophy Association, (MDA) United States, and the Federation Foundation of Greater Philadelphia., We thank Dr. Helene Catoire and Dr. Martine Therrien for their technical support on C. elegans., and Courcelles, Michel

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Mutant, RNA replacement therapy, Biology, ribozymes, Article, Oculopharyngeal muscular dystrophy, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, microRNA, medicine, Gene knockdown, Messenger RNA, polyalanine disorders, PABPN1, lcsh:RM1-950, Ribozyme, RNA, medicine.disease, 3. Good health, Cell biology, microRNAs, [SDV] Life Sciences [q-bio], 030104 developmental biology, lcsh:Therapeutics. Pharmacology, 030220 oncology & carcinogenesis, OPMD, biology.protein, Molecular Medicine, C2C12
Abstract

Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of a short polyalanine (polyAla) tract in the poly(A)-binding protein nuclear 1 protein (PABPN1). Despite the monogenic nature of OPMD, no treatment is currently available. Here we report an RNA replacement strategy that has therapeutic potential in cell and C. elegans OPMD models. We develop selective microRNAs (miRNAs) against PABPN1, and we report that miRNAs and our previously developed hammerhead ribozymes (hhRzs) are capable of reducing the expression of both the mRNA and protein levels of PABPN1 by as much as 90%. Since OPMD derives from a very small expansion of GCG within the polyAla tract, our hhRz and miRNA molecules cannot distinguish between the wild-type and mutant mRNAs of PABPN1. Therefore, we designed an optimized-codon wild-type PABPN1 (opt-PABPN1) that is resistant to cleavage by hhRzs and miRNAs. Co-expression of opt-PABPN1 with either our hhRzs or miRNAs restored the level of PABPN1, concomitantly with a reduction in expanded PABPN1-associated cell death in a stable C2C12 OPMD model. Interestingly, knockdown of the PABPN1 by selective hhRzs in the C. elegans OPMD model significantly improved the motility of the PABPN1-13Ala worms. Taken together, RNA replacement therapy represents an exciting approach for OPMD treatment., Graphical Abstract

Published
2019

6. KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects

Author

Salim Benlefki, Jean-Pierre Bouchard, Melissa Bowerman, Véronique Bernard, Eric Delpire, Claire Soulard, Annie Dionne, Guy A. Rouleau, Pascale Hince, William Camu, Patrick A. Dion, Emmanuelle Coque, Céline Salsac, Gillian Butler-Browne, Frédérique Scamps, Cédric Raoul, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), ANR-14-RARE-0006,FaSMALS,Common Pathogenic Pathways and Therapeutics for SMA and ALS motoneuron diseases(2014), ANR-14-CE36-0009,GliALS,From knowledge base of the pathogenic astrocyte-motoneuron communication in amyotrophic lateral sclerosis to therapeutic approaches(2014), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine, McGill University = Université McGill [Montréal, Canada], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, Na+/K+ ATPase, Axonal loss, Neuromuscular junction, Q1, Synaptic Transmission, 0302 clinical medicine, Andermann syndrome, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Denervation, Motor Neurons, Neurotransmitter Agents, Symporters, musculoskeletal, neural, and ocular physiology, Peripheral Nervous System Diseases, Chloride homeostasis, Motoneuron, medicine.anatomical_structure, Carbamazepine, Neurology, Spinal Cord, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sodium-Potassium-Exchanging ATPase, Presynaptic Terminals, Mice, Transgenic, Biology, Neurotransmission, lcsh:RC321-571, 03 medical and health sciences, Na$^+$/K$^+$ ATPase, Atrophy, Chlorides, medicine, Animals, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Amyotrophy, medicine.disease, R1, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Peripheral neuropathy, nervous system, Agenesis of Corpus Callosum, Electrical activity, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na$^+$/K$^+$-ATPase $\alpha$1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na$^+$/K$^+$-ATPase $\alpha$1 localization and reduces NMJ denervation in $Slc12a6^{-/-}$ mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome.

Published
2017

7. Analysis of DNAJC13 mutations in French-Canadian/French cohort of Parkinson's disease

Author

Michel Boivin, Mélanie Langlois, Patrick A. Dion, Yves Dauvilliers, Stephanie Strong, Guy A. Rouleau, Nicolas Dupré, Claire S. Leblond, Amirthagowri Ambalavanan, Ziv Gan-Or, Alexandre Dionne-Laporte, Dan Spiegelman, Jay P. Ross, Emmanuelle Pourcher, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Adult, Male, Aging, medicine.medical_specialty, Canada, Parkinson's disease, Disease, Bioinformatics, White People, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, Genetic Association Studies, Aged, Паркинсона болезнь, DNAJC13, business.industry, General Neuroscience, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Parkinson Disease, Odds ratio, Sequence Analysis, DNA, Middle Aged, medicine.disease, DNAJC13, ген, 030104 developmental biology, Cohort, Mutation, French canadian, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, MIPs, Developmental Biology, Cohort study, Molecular Chaperones
Abstract

International audience; DNAJC13 mutations have been suggested to cause Parkinson's disease (PD), yet subsequent studies reported conflicting results on this association. In the present study, we sequenced the coding region of DNAJC13 in a French-Canadian/French cohort of 528 PD patients and 692 controls. A total of 62 (11.7%) carriers of rare DNAJC13 variants were identified among the PD patients compared with 82 (11.8%) among controls (p = 1.0). Two variants that were previously suggested to be associated with PD, p.R1516H and p.L2170W, were identified with similar directions of association as previously reported. The p.R1516H was found in 2 (0.4%) patients versus 6 (0.9%, nonsignificant) controls and the p.L2170W variant was found in 9 (1.7%) patients and 5 (0.7%, nonsignificant) controls. Meta-analysis with previous reports resulted in odds ratios of 0.32 (95% confidence interval = 0.15-0.68, p = 0.0037) and 2.68 (95% confidence interval = 1.32-5.42, p = 0.007), respectively. Our results provide some support for the possibility that specific DNAJC13 variants may play a minor role in PD susceptibility, although studies in additional populations are necessary.

Published
2016

8. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis

Author

Patrick A. Dion, Daniel Rochefort, Veronique V. Belzil, Pascale Hince, Catherine André-Guimont, Andrew W. Folkmann, Annie Levert, Susan R. Wente, Hannah M. Kaneb, Guy A. Rouleau, Anne Noreau, Hussein Daoud, William Camu, Sabrina Vidal, Li-En Jao, Anna Szuto, Jean-Pierre Bouchard, Claire S. Leblond, Nicolas Dupré, Simon Girard, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Nucleocytoplasmic Transport Proteins, Messenger, Haploinsufficiency, Neurodegenerative, medicine.disease_cause, Medical and Health Sciences, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Amyotrophic lateral sclerosis, Zebrafish, Genetics (clinical), Genetics & Heredity, Genetics, Arthrogryposis, Motor Neurons, Microscopy, 0303 health sciences, Mutation, Microscopy, Confocal, biology, General Medicine, Articles, Biological Sciences, 3. Good health, Pedigree, DNA-Binding Proteins, Codon, Nonsense, Confocal, Neurological, Lethal arthrogryposis with anterior horn cell disease, RNA Splicing, Nonsense mutation, Mutation, Missense, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Codon, Molecular Biology, Protein Processing, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Animal, Lethal congenital contracture syndrome, Amyotrophic Lateral Sclerosis, Post-Translational, Neurosciences, biology.organism_classification, medicine.disease, Brain Disorders, Disease Models, Animal, Orphan Drug, Nonsense, Hela Cells, Disease Models, Nuclear Pore, RNA, Missense, ALS, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, HeLa Cells
Abstract

International audience; Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.

Published
2015

9. Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/beta-catenin pathway

Author

Bernard Brais, Daniel Rochefort, Christian Neri, Aida Abu-Baker, Guy A. Rouleau, Patrick A. Dion, Rébecca Gaudet, Janet L Laganière, Biologie et Pathologie du Neurone (Brain-C), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Muscular Dystrophy Association (MDA), Canadian Institute of Health Research, Federation Foundation of Greater Philadelphia, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, lithium chloride (LiCl), Poly(A)-Binding Protein I, Myoblasts, Mice, 0302 clinical medicine, GSK-3, beta-catenin (β-catenin), Lymphocytes, beta-catenin (beta-catenin), Muscular dystrophy, Wnt Signaling Pathway, Tissue homeostasis, beta Catenin, 0303 health sciences, Cell Death, Wnt signaling pathway, Cell Differentiation, poly (A) binding protein nuclear 1 (PABPN1), 3. Good health, Cell biology, Protein Transport, Original Article, Signal transduction, C2C12, Cell Survival, Immunology, Green Fluorescent Proteins, Wnt pathway, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Oculopharyngeal muscular dystrophy, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, Muscular Dystrophy, Oculopharyngeal, medicine, Animals, Humans, 030304 developmental biology, Cell Proliferation, Cell Nucleus, Dose-Response Relationship, Drug, Cell Biology, medicine.disease, Molecular biology, oculopharyngeal muscular dystrophy (OPMD), Catenin, Mutant Proteins, Lithium Chloride, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract

International audience; Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 ((exp)PABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (beta-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3 beta. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3 beta inhibitor, and observed the enhanced expression of beta-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the (exp)PABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing (exp)PABPN1. A similar effect on beta-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/beta-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD.

Published
2013

10. HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K(+)/Cl(-) co-transporter 3

Author

Daniel Rochefort, Claudia Gaspar, Pascale Hince, Patrick A. Dion, Masoud Shekarabi, Jean-Yves Lapointe, Sandra Dacal, Adèle Salin-Cantegrel, Liliane Karemera, Guy A. Rouleau, Sébastien Holbert, Janet Laganière, Department of Medicine, Université de Montréal (UdeM), Canadian Institutes of Health Research (CIHR grant no. 172248), and Fondation des jumelles Coudé

Subjects
KCC3, Xenopus, medicine.disease_cause, ASTROCYTES, Mice, Xenopus laevis, 0302 clinical medicine, Genetics (clinical), 0303 health sciences, Mutation, Symporters, biology, Kinase, Brain, General Medicine, Transfection, 3. Good health, Cell biology, RECEPTORS, Glutathione S-transferase, Biochemistry, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hereditary motor and sensory neuropathy, Protein Binding, Molecular Sequence Data, METABOLISM, CLONING, 03 medical and health sciences, CELL-VOLUME REGULATION, Two-Hybrid System Techniques, Creatine Kinase, BB Form, Genetics, medicine, Animals, Humans, Amino Acid Sequence, Molecular Biology, 030304 developmental biology, IDENTIFICATION, Transporter, biology.organism_classification, medicine.disease, K+-CL-COTRANSPORTER, ATP RELEASE, CORPUS-CALLOSUM, Oocytes, biology.protein, Creatine kinase, Hereditary Sensory and Motor Neuropathy, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells
Abstract

International audience; The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in the development of the nervous system remain poorly understood. The functional regulation of this transporter by protein partners is also largely unknown. Using a yeast two-hybrid approach, we discovered that the C-terminal domain (CTD) of KCC3, which is lost in most HMSN/ACC-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CK-B was further confirmed by in vitro glutathione S-transferase pull-down assay, followed by sequencing of the pulled-down complexes. In transfected cultured cells, immunofluorescence labeling showed that CK-B co-localizes with wild-type KCC3, whereas the kinase fails to interact with the inactive truncated KCC3. Finally, CK-B's inhibition by DNFB results in reduction of activity of KCC3 in functional assays using Xenopus laevis oocytes. This physical and functional association between the co-transporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of HMSN/ACC.

Published
2008

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