Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder

Am J Hum Genet. 2005 Dec;77(6):1086-91. doi: 10.1086/498176. Epub 2005 Oct 11.


Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this disorder.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Chromosome Mapping
  • Chromosomes, Human, X*
  • Cohort Studies
  • DNA, Mitochondrial / genetics*
  • Female
  • Gene Frequency
  • Genetic Markers
  • Haplotypes*
  • Heterozygote
  • Homozygote
  • Humans
  • Linear Models
  • Linkage Disequilibrium
  • Male
  • Microsatellite Repeats
  • Mitochondrial Diseases / epidemiology*
  • Mitochondrial Diseases / genetics*
  • Optic Atrophy, Hereditary, Leber / epidemiology
  • Optic Atrophy, Hereditary, Leber / genetics
  • Pedigree
  • Penetrance
  • Phenotype*
  • Point Mutation
  • Polymorphism, Restriction Fragment Length
  • Sex Factors
  • Statistics, Nonparametric


  • DNA, Mitochondrial
  • Genetic Markers