title: Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis.
abstract: Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.forename: Janet
authors.initials: J
authors.lastname: Cady
authors.forename: Craig
authors.initials: C
authors.lastname: Zaidman
authors.forename: Paul
authors.initials: P
authors.lastname: Cooper
authors.forename: Taha
authors.initials: T
authors.lastname: Bali
authors.forename: Peggy
authors.initials: P
authors.lastname: Allred
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Michael
authors.initials: M
authors.lastname: Baughn
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Libby
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics* / Q000502:physiology*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins