Subnormal levels of POLγA cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia [corrected]

Hum Mol Genet. 2013 Jun 15;22(12):2411-22. doi: 10.1093/hmg/ddt094. Epub 2013 Feb 27.


The POLG1 gene encodes the catalytic subunit of mitochondrial DNA (mtDNA) polymerase γ (POLγ). We here describe a sibling pair with adult-onset progressive external ophthalmoplegia, cognitive impairment and mitochondrial myopathy characterized by DNA depletion and multiple mtDNA deletions. The phenotype is due to compound heterozygous POLG1 mutations, T914P and the intron mutation c.3104 + 3A > T. The mutant genes produce POLγ isoforms with heterozygous phenotypes that fail to synthesize longer DNA products in vitro. However, exon skipping in the c.3104 + 3A > T mutant is not complete, and the presence of low levels of wild-type POLγ explains patient survival. To better understand the underlying pathogenic mechanisms, we characterized the effects of POLγ depletion in vitro and found that leading-strand DNA synthesis is relatively undisturbed. In contrast, initiation of lagging-strand DNA synthesis is ineffective at lower POLγ concentrations that uncouples leading strand from lagging-strand DNA synthesis. In vivo, this effect leads to prolonged exposure of the heavy strand in its single-stranded conformation that in turn can cause the mtDNA deletions observed in our patients. Our findings, thus, suggest a molecular mechanism explaining how POLγ mutations can cause mtDNA deletions in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • DNA Polymerase gamma
  • DNA Replication*
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Exons
  • Female
  • Genes, Dominant
  • Heterozygote
  • Humans
  • Introns
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Ophthalmoplegia, Chronic Progressive External / enzymology*
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Ophthalmoplegia, Chronic Progressive External / metabolism
  • Pedigree
  • Point Mutation
  • Sequence Deletion


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