1. Les mutations du gène TMEM240 provoquent l'ataxie spinocérébelleuse 21 avec un retard mental et des troubles cognitifs sévères
- Author
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Giovanni Stevanin, Luc Buée, Olivier Sand, David Devos, Guillaume Grolez, Marie Lorraine Monin, Alexandra Durr, Caroline Moreau, Kathy Dujardin, Bernard Sablonnière, Vincent Huin, Alexis Brice, Cyril Goizet, Alexandre Genet, Alain Destée, Mathieu Anheim, Perrine Charles, Christine Delmaire, Jérôme Delplanque, Isabelle Strubi-Vuillaume, Delphine Dellacherie, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie Pathologie [CHRU Lille] (Pôle de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Departement de Neuroradiologie [Lille], Service de neuropédiatrie [CHU Lille], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and HESAM Université (HESAM)
- Subjects
Cerebellum ,MESH: Intellectual Disability / genetics ,MESH: Introns ,MESH: Exome / genetics ,MESH: Amino Acid Sequence ,MESH: Membrane Proteins / genetics ,MESH: Spinocerebellar Degenerations / pathology ,Autosomal dominant cerebellar ataxia ,MESH: Child ,Missense mutation ,MESH: DNA Mutational Analysis ,Exome ,MESH: Spinocerebellar Degenerations / psychology ,MESH: Cohort Studies ,Exome sequencing ,Genetics ,MESH: Conserved Sequence ,MESH: Membrane Proteins / physiology ,MESH: Neuropsychological Tests ,MESH: Cognition Disorders / psychology ,MESH: Infant ,3. Good health ,medicine.anatomical_structure ,MESH: Young Adult ,Spinocerebellar ataxia ,medicine.symptom ,MESH: Spinocerebellar Degenerations / genetics ,MESH: Mutation / physiology ,congenital, hereditary, and neonatal diseases and abnormalities ,Ataxia ,MESH: Pedigree ,MESH: Age of Onset ,MESH: Genetic Linkage ,Biology ,MESH: Intellectual Disability / psychology ,MESH: Chromosomes, Human, Pair 1 / genetics ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,medicine ,Quantitative Biology - Genomics ,Genomics (q-bio.GN) ,MESH: Adolescent ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,MESH: Molecular Sequence Data ,Cerebellar ataxia ,[SCCO.NEUR]Cognitive science/Neuroscience ,MESH: Child, Preschool ,MESH: Polymerase Chain Reaction ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,MESH: Male ,MESH: France ,MESH: Cognition Disorders / genetics ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,FOS: Biological sciences ,TMEM240 ,Neurology (clinical) ,MESH: Intelligence Tests ,MESH: Female ,exome - Abstract
Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240 , was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment. * Abbreviations : SCA : spinocerebellar ataxia SPATAX : network of hereditary forms of spastic paraplegias and cerebellar ataxias
- Published
- 2014
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