Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain

Neurology. 2003 Oct 14;61(7):903-8. doi: 10.1212/


Objective: To better understand the still unknown pathologic mechanism involved in the accumulation of multiple mtDNA deletions in stable tissues.

Methods: A large-scale screening of mtDNA molecules from skeletal muscle was performed in 14 patients with progressive external ophthalmoplegia (PEO) and 2 patients with mitochondrial neurogastrointestinal encephalomyopathy carrying mutations on ANT1, C10ORF2 or POLG1, and TP genes.

Results: Patients with at least one mutation in the exonuclease domain of POLG1 showed the highest frequency of individually rare point mutations only in the mtDNA control region; in addition, high levels, in terms of frequency and heteroplasmy, of recurrent mutations (A189G, T408A, and T414G) and alterations affecting the (HT)D310 region were detectable in many of the patients. Two homozygous POLG1 mutations, within the exonuclease domain, were able to induce an increased mutational burden also in fibroblasts from patients with PEO.

Conclusions: Specific POLG1 mutations directly affect the integrity of the mtDNA by reducing its proof-reading exonuclease activity, resulting in the accumulation of heteroplasmic levels of both randomly rare and recurrent point mutations in the skeletal muscle tissue and fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotide Translocator 1 / genetics
  • DNA Helicases
  • DNA Mutational Analysis
  • DNA Polymerase gamma
  • DNA Primase / genetics
  • DNA Repair / genetics
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / genetics
  • Homozygote
  • Humans
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Proteins
  • Muscle, Skeletal / metabolism*
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Point Mutation / genetics
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology


  • Adenine Nucleotide Translocator 1
  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • DNA Primase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human
  • DNA Helicases
  • TWNK protein, human