title: Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma.
abstract: 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.
authors.affiliation: Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Alistair T
authors.initials: AT
authors.lastname: Pagnamenta
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Neil E
authors.initials: NE
authors.lastname: Anderson
authors.forename: Rosetta
authors.initials: R
authors.lastname: Marotta
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Duncan
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Adrienne
authors.initials: A
authors.lastname: Laskowski
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: 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
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase