Mitochondrial DNA copy number and D-loop region methylation in carriers of amyotrophic lateral sclerosis gene mutations

Epigenomics. 2018 Nov;10(11):1431-1443. doi: 10.2217/epi-2018-0072. Epub 2018 Aug 8.

Abstract

Aim: To investigate mitochondrial DNA (mtDNA) copy number and D-loop region methylation in carriers of SOD1, TARDBP, FUS and C9orf72 mutations.

Methods: Investigations were performed in blood DNA from 114 individuals, including amyotrophic lateral sclerosis (ALS) patients, presymptomatic carriers and noncarrier family members.

Results: Increased mtDNA copy number (p = 0.0001) was observed in ALS patients, and particularly in those with SOD1 or C9orf72 mutations. SOD1 mutation carriers showed also a significant decrease in D-loop methylation levels (p = 0.003). An inverse correlation between D-loop methylation levels and the mtDNA copy number (p = 0.0005) was observed.

Conclusion: Demethylation of the D-loop region could represent a compensatory mechanism for mtDNA upregulation in carriers of ALS-linked SOD1 mutations.

Keywords: D-loop mitochondrial region; SOD1; amyotrophic lateral sclerosis; epigenetics; mitochondrial DNA methylation; mtDNA copy number.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein / genetics
  • DNA Copy Number Variations*
  • DNA Methylation*
  • DNA, Mitochondrial / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • RNA-Binding Protein FUS / genetics
  • Superoxide Dismutase-1 / genetics

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • FUS protein, human
  • RNA-Binding Protein FUS
  • SOD1 protein, human
  • TARDBP protein, human
  • Superoxide Dismutase-1