Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction

Trends Genet. 2003 May;19(5):257-62. doi: 10.1016/S0168-9525(03)00072-6.


Here we define a category of human, maternally inherited disorders that are characterized by a homoplasmic mtDNA pathogenic mutation with variable penetrance and a stereotypical clinical expression, usually restricted to a single tissue. Examples of such disorders include Leber's hereditary optic neuropathy, mitochondrial non-syndromic sensorineural hearing loss, and a form of mitochondrial hypertrophic cardiomyopathy. The mtDNA mutation is necessary, but not sufficient to induce the pathology, and multiple lines of evidence suggest a two-locus genetic model involving a primary mitochondrial mutation and a nuclear modifier. The nuclear modifier does not induce any pathology per se, but it contributes to the pathogenic effect of the mitochondrial mutation. The nuclear modifier could be a common functional polymorphism in a tissue-specific protein, possibly with mitochondrial location.

Publication types

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

MeSH terms

  • Animals
  • Cardiomyopathy, Hypertrophic
  • Cell Nucleus / genetics*
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • Female
  • Genetic Markers / genetics
  • Hearing Loss, Sensorineural / congenital
  • Hearing Loss, Sensorineural / genetics
  • Humans
  • Male
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mutation*
  • Optic Atrophy, Hereditary, Leber / genetics


  • DNA, Mitochondrial
  • Genetic Markers