1. A mutation that creates a pseudoexon in SOD1 causes familial ALS
- Author
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Guy A. Rouleau, Pierre Clavelou, Benoît Funalot, Philippe Couratier, Paul N Valdmanis, Patrick A. Dion, Judith St-Onge, Pascale Hince, William Camu, Veronique V. Belzil, James Lee, Center of Excellence in Neuroscience, CHU de Montréal, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Biomolécules Thérapies anti-tumorales (EA4021), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Neurologie [CHU Limoges], Service de Neurologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Centre référent Sclérose Latérale Amyotrophique, Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM)
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MESH: Mutation ,MESH: Pedigree ,Chromosomes, Human, Pair 21 ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,SOD1 ,Molecular Sequence Data ,Locus (genetics) ,MESH: Base Sequence ,Biology ,03 medical and health sciences ,Exon ,0302 clinical medicine ,MESH: Chromosomes, Human, Pair 21 ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,Intronic Mutation ,medicine ,Humans ,Amyotrophic lateral sclerosis ,MESH: Amyotrophic Lateral Sclerosis ,MESH: Superoxide Dismutase ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,MESH: Humans ,MESH: Molecular Sequence Data ,Base Sequence ,Superoxide Dismutase ,Alternative splicing ,Amyotrophic Lateral Sclerosis ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Exons ,medicine.disease ,Molecular biology ,Stop codon ,3. Good health ,Pedigree ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH: Exons ,Chromosome 21 ,030217 neurology & neurosurgery - Abstract
International audience; Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease which targets motor neurons of the cortex, brainstem and spinal cord. About 5-10% of all amyotrophic lateral sclerosis cases are familial (FALS), and 15-20% of FALS cases are caused by mutations in the zinc-copper superoxide dismutase gene (SOD1). We identified a large family from France with ten members affected with ALS. Linkage was established to the SOD1 locus on chromosome 21 and genomic and cDNA sequencing was performed for the SOD1 gene. This revealed an activated pseudoexon between exons 4 and 5 that was present in two tested members of the family. Translation of this 43 base pair exon results in the introduction of seven amino acids before a stop codon is present, leading to a prematurely truncated SOD1 protein product of 125 amino acids. Sequencing intron 4 in a patient revealed a eterozygous change 304 bp before exon 5 (c.358 - 304C > G), but only 5 bp after the cryptic exon, thus causing this alternative splice product. This mutation segregated in all affected individuals of the family. This adds an additional genetic mechanism for developing OD1-linked ALS and is one which can be more readily targeted by gene therapy.
- Published
- 2009
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