Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

J Med Genet. 2009 Mar;46(3):209-14. doi: 10.1136/jmg.2008.058180.


Background: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease.

Methods and results: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids.

Conclusion: The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Cytochrome-c Oxidase Deficiency / genetics
  • Cytochrome-c Oxidase Deficiency / pathology
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / genetics*
  • Diffuse Cerebral Sclerosis of Schilder / genetics
  • Diffuse Cerebral Sclerosis of Schilder / pathology
  • Female
  • Humans
  • Infant
  • Liver / ultrastructure
  • Male
  • Middle Aged
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology
  • Muscle, Skeletal / ultrastructure
  • Mutation, Missense
  • Ophthalmoplegia, Chronic Progressive External / genetics
  • Ophthalmoplegia, Chronic Progressive External / pathology
  • Sequence Alignment


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