title: Screening for rare variants in the coding region of ALS-associated genes at 9p21.2 and 19p13.3.
abstract: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a, IFNK, MOBKL2b, and C9ORF72. A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a, IFNK, MOBKL2b, and C9ORF72 are unlikely to be a genetic cause of ALS.
authors.affiliation: Rudolf Magnus Institute of Neuroscience, Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Koppers
authors.forename: Ewout J N
authors.initials: EJ
authors.lastname: Groen
authors.forename: Paul W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: Wouter
authors.initials: W
authors.lastname: van Rheenen
authors.forename: Esther
authors.initials: E
authors.lastname: Witteveen
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology* / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D005820:Genetic Testing / Q000706:statistics & numerical data; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D012307:Risk Factors
chemical_list: D005819:Genetic Markers