Published online 4 June 2004
Nucleic Acids Research, 2004, Vol. 32, No. 10 3053-3064
© 2004 Oxford University Press
Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA
Institute of Medical Technology and Tampere University Hospital, Tampere, Finland, 1 Programme of Neurosciences and Department of Neurology, Biomedicum-Helsinki, Helsinki University, Helsinki, Finland and 2 Department of Molecular Genetics (VIB8), Flanders Interuniversity Institute for Biotechnology and Born-Bunge Foundation, University of Antwerp, Antwerpen, Belgium
*To whom correspondence should be addressed. Tel: +358 3 2158598; Fax: +358 3 2157710; Email: lthasp{at}uta.fi
Received January 19, 2004; Revised April 6, 2004;; Accepted May 12, 2004
Autosomal dominant and/or recessive progressive external ophthalmoplegia (ad/arPEO) is associated with mtDNA mutagenesis. It can be caused by mutations in three nuclear genes, encoding the adenine nucleotide translocator 1, the mitochondrial helicase Twinkle or DNA polymerase 
(POLG). How mutations in these genes result in progressive accumulation of multiple mtDNA deletions in post- mitotic tissues is still unclear. A recent hypothesis suggested that mtDNA replication infidelity could promote slipped mispairing, thereby stimulating deletion formation. This hypothesis predicts that mtDNA of ad/arPEO patients will contain frequent mutations throughout; in fact, our analysis of muscle from ad/arPEO patients revealed an age-dependent, enhanced accumulation of point mutations in addition to deletions, but specifically in the mtDNA control region. Both deleted and non-deleted mtDNA molecules showed increased point mutation levels, as did mtDNAs of patients with a single mtDNA deletion, suggesting that point mutations do not cause multiple deletions. Deletion breakpoint analysis showed frequent breakpoints around homopolymeric runs, which could be a signature of replication stalling. Therefore, we propose replication stalling as the principal cause of deletion formation.
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