Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion

Am J Hum Genet. 2013 Jun 6;92(6):981-9. doi: 10.1016/j.ajhg.2013.04.017. Epub 2013 May 23.


The G4C2 repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G4C2 repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5' of the G4C2 repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • Base Sequence
  • Case-Control Studies
  • CpG Islands*
  • DNA Methylation*
  • DNA Repeat Expansion
  • Genetic Association Studies
  • Heterozygote
  • Humans
  • Linear Models
  • Membrane Proteins / genetics*
  • Middle Aged
  • Molecular Sequence Data
  • Pedigree
  • Sequence Analysis, DNA
  • Tumor Suppressor Proteins / genetics*


  • Membrane Proteins
  • TMEM8B protein, human
  • Tumor Suppressor Proteins