Clinical and molecular features of POLG-related mitochondrial disease

Cold Spring Harb Perspect Biol. 2013 Apr 1;5(4):a011395. doi: 10.1101/cshperspect.a011395.

Abstract

The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • DNA Polymerase gamma
  • DNA Replication
  • DNA, Mitochondrial*
  • DNA-Directed DNA Polymerase / metabolism
  • DNA-Directed DNA Polymerase / physiology*
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease
  • Humans
  • Mice
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism*
  • Mutagenesis
  • Mutation
  • Oxidative Stress
  • Phenotype

Substances

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