Progressive external ophthalmoplegia (PEO) is an autosomal mitochondrial disorder associated with depletion of the mitochondrial genome and/or the accumulation of mutations and deletions within mtDNA. In May 3 Journal of Biological Chemistry, Mikhail Ponamarev and colleagues from National Institutes of Health, North Carolina, show that a point mutation in the mitochondrial DNA polymerase γ (pol γ) causes error-prone DNA synthesis in PEO (J Biol Chem 2002, 277:15225-15228).

Ponamarev et al. analyzed the effects of the 955 codon (Y955C) mutation in the pol γ gene on the kinetics and fidelity of DNA synthesis. They observed that the Y955C enzyme retains a wild-type catalytic rate but suffers a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate. In addition, the full mutator effect of the Y955C substitution was revealed by genetic inactivation of the exonuclease, and error rates for certain mismatches were elevated by 10-100-fold....