Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis

Matthew B. Harms, Janet Cady, Craig Zaidman, Paul Cooper, Taha Bali, Peggy Allred, Carlos Cruchaga, Michael Baughn, Ryan T. Libby, Alan Pestronk, Alison Goate, John Ravits, Robert H. Baloh

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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.

Original languageEnglish
Pages (from-to)2234.e13-2234.e19
JournalNeurobiology of Aging
Volume34
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • Amyotrophic lateral sclerosis
  • C9ORF72
  • C9ORF72 hexanucleotide repeat
  • Genetics

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