Hum. Reprod. Advance Access first published online on April 4, 2006
This version published online on August 28, 2006
Human Reproduction, doi:10.1093/humrep/del076
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1 Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, WC1N 1EH, UK
* To whom correspondence should be addressed. 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. This is a new version of this article as it has now been highlighted as a fast-track article.
Received January 17, 2006
Revised February 16, 2006
Accepted February 22, 2006
Fast Track Article
Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma
Alistair T. Pagnamenta 1, Jan-Willem Taanman 2, Callum J. Wilson 3, Neil E. Anderson 3, Rosetta Marotta 4, Andrew J. Duncan 1, Maria Bitner-Glindzicz 5, Robert W. Taylor 6, Adrienne Laskowski 7, David R. Thorburn 7, and Shamima Rahman 1 *
2 University Department of Clinical Neurosciences, Royal Free and University College Medical School, NW3 2PF, London, UK
3 Department of Neurology, Auckland City Hospital, Private Bag 92024, Auckland, New Zealand
4 Centre for Clinical Neurosciences and Neurological Research, St Vincent’s Hospital, Melbourne, VIC 3065, Australia
5 Clinical and Molecular Genetics Unit, Institute of Child Health, Guilford St., London, WC1N 1EH, UK
6 Mitochondrial Research Group, University of Newcastle upon Tyne, Newcastle, NE2 4HH, UK
7 Murdoch Children’s Research Institute, Royal Children’s Hospital and Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
Shamima Rahman, E-mail: s.rahman{at}ich.ucl.ac.uk
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