A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits

Mitochondrion. 2012 Mar;12(2):313-9. doi: 10.1016/j.mito.2011.11.006. Epub 2011 Dec 4.

Abstract

Human mitochondrial DNA (mtDNA) polymerase γ (pol γ) is the sole enzyme required to replicate and maintain the integrity of the mitochondrial genome. It comprises two subunits, a catalytic p140 subunit and a smaller p55 accessory subunit encoded by the POLG2 gene. We describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with adPEO and multiple mtDNA deletions. Biochemical studies of the recombinant mutant p55 protein showed a reduced affinity to the pol γ p140 subunit, leading to impaired processivity of the holoenzyme complex but did not show sensitivity to N-ethylmalaimide (NEM) inhibition, inferring a novel disease mechanism.

Publication types

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

MeSH terms

  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism*
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Ophthalmoplegia, Chronic Progressive External / pathology
  • Protein Binding
  • Protein Multimerization*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Sequence Deletion*

Substances

  • DNA, Mitochondrial
  • Protein Subunits
  • DNA-Directed DNA Polymerase
  • POLGbeta protein, human