title: Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA.
abstract: 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 gamma (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.
authors.affiliation: Institute of Medical Technology and Tampere University Hospital, Tampere, Finland.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Wanrooij
authors.forename: Petri
authors.initials: P
authors.lastname: Luoma
authors.forename: Gert
authors.initials: G
authors.lastname: van Goethem
authors.forename: Christine
authors.initials: C
authors.lastname: van Broeckhoven
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D002675:Child, Preschool; D045303:Cytochromes b / Q000235:genetics; D004265:DNA Helicases; D000074002:DNA Polymerase gamma; D019915:DNA Primase / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D019901:Locus Control Region / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D016296:Mutagenesis / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D045303:Cytochromes b; D019915:DNA Primase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D004265:DNA Helicases; C431576:TWNK protein, human