Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma

BACKGROUND: Premature ovarian failure (POF) results in menopause before the age of 40. Recently, mutations in the catalytic subunit of mitochondrial DNA polymerase gamma (POLG) were shown to segregate with POF in families with progressive external ophthalmoplegia (PEO) and multiple large-scale rearrangements of mitochondrial DNA (mtDNA). METHODS AND RESULTS: A patient, mother and maternal grandmother are described, all presenting with POF and PEO. The mother developed parkinsonism in her sixth decade. Normal mtDNA sequence excluded mitochondrial inheritance. Sequence analysis of polymerase gamma revealed a dominant Y955C mutation that segregated with disease. Southern blot analysis demonstrated mtDNA depletion in fibroblasts (43% of controls). In contrast, multiple rearrangements of mtDNA were seen in skeletal muscle, consistent with the relative sparing of nuclear-encoded complex II activity compared with other respiratory chain enzymes. Immunoblotting of native gels showed that DNA polymerase gamma stability was not affected, whereas a reverse-transcriptase primer-extension assay suggested a trend towards reduced polymerase activity in fibroblasts. CONCLUSIONS: This study confirms that POLG mutations can segregate with POF and parkinsonism and demonstrates for the first time that the Y955C mutation can lead to mtDNA depletion. Future screening projects will determine the frequency with which POLG is involved in the aetiology of POF and its impact on reproductive counselling.