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).


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.
Pagnamenta
Alistair T
AT
Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, WC1N 1EH, UK.
Taanman
Jan-Willem
JW
Wilson
Callum J
CJ
Anderson
Neil E
NE
Marotta
Rosetta
R
Duncan
Andrew J
AJ
Bitner-Glindzicz
Maria
M
Taylor
Robert W
RW
Laskowski
Adrienne
A
Thorburn
David R
DR
Rahman
Shamima
S
D000328:Adult; D000368:Aged; D000074002:DNA Polymerase gamma; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005091:Exons; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007438:Introns; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000235:genetics; D018482:Muscle, Skeletal / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D016649:Primary Ovarian Insufficiency / Q000201:enzymology* / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D014202:Tremor / Q000235:genetics
D017931:DNA Primers; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase