Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia

Nat Struct Mol Biol. 2004 Aug;11(8):770-6. doi: 10.1038/nsmb805. Epub 2004 Jul 18.


Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma). Four autosomal dominant mutations that cause PEO encode the amino acid substitutions G923D, R943H, Y955C and A957S in the polymerase domain of pol gamma. A homology model of the pol gamma catalytic domain in complex with DNA was developed to investigate the effects of these mutations. Two mutations causing the most severe disease phenotype, Y955C and R943H, change residues that directly interact with the incoming dNTP. Polymerase mutants exhibit 0.03-30% wild-type polymerase activity and a 2- to 35-fold decrease in nucleotide selectivity in vitro. The reduced selectivity and catalytic efficiency of the autosomal dominant PEO mutants predict in vivo dysfunction, and the extent of biochemical defects correlates with the clinical severity of the disease.

MeSH terms

  • Amino Acid Motifs
  • Bacterial Proteins / chemistry
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / metabolism
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / metabolism
  • Genes, Dominant
  • Glycine / chemistry
  • Humans
  • Kinetics
  • Mitochondria / enzymology*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation
  • Nucleotides / chemistry
  • Ophthalmoplegia, Chronic Progressive External / enzymology
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Protein Binding
  • Protein Folding
  • RNA-Directed DNA Polymerase / metabolism
  • Structure-Activity Relationship
  • Tyrosine / chemistry


  • Bacterial Proteins
  • Nucleotides
  • Tyrosine
  • DNA
  • RNA-Directed DNA Polymerase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Glycine

Associated data

  • PDB/1D8Y
  • PDB/1T7P
  • PDB/2KTQ
  • PDB/3DBP