Mitochondrial DNA polymerase-gamma and human disease

Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R244-52. doi: 10.1093/hmg/ddl233.


The maintenance of mitochondrial DNA (mtDNA) is critically dependent upon polymerase-gamma (pol-gamma), encoded by the nuclear gene POLG. Over the last 5 years, it has become clear that mutations of POLG are a major cause of human disease. Secondary mtDNA defects characterize these disorders, with mtDNA depletion, multiple mtDNA deletions or multiple point mutations of mtDNA in clinically affected tissues. The secondary mtDNA defects cause cell and tissue-specific deficiencies of mitochondrial oxidative phosphorylation, leading to organ dysfunction and human disease. Functional genetic variants of POLG are present in up to approximately 0.5% of the general population, and pathogenic mutations have been described in most exons of the gene. Clinically, POLG mutations can present from early neonatal life to late middle age, with a spectrum of phenotypes that includes common neurological disorders such as migraine, epilepsy and Parkinsonism. Transgenic mice and biochemical studies of recombinant mutated proteins are helping to unravel mechanisms of pathogenesis, and patterns are beginning to emerge relating genotype to phenotype.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • DNA Polymerase gamma
  • DNA Replication
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Genes, Dominant
  • Genes, Recessive
  • Humans
  • Infertility, Male / enzymology
  • Infertility, Male / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Models, Biological
  • Mutation
  • Phenotype
  • Syndrome


  • DNA, Mitochondrial
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human