Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA
| Autor: | Petri Luoma, Anu Suomalainen, Sjoerd Wanrooij, Johannes N. Spelbrink, Gert Van Goethem, Christine Van Broeckhoven |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
Adult
DNA Replication Male Mitochondrial DNA Aging Ophthalmoplegia Chronic Progressive External DNA polymerase Mutagenesis (molecular biology technique) DNA Primase DNA-Directed DNA Polymerase medicine.disease_cause Human mitochondrial genetics DNA Mitochondrial Mitochondrial Proteins Genetics medicine Humans Muscle Skeletal Gene Aged Sequence Deletion mtDNA control region Mutation biology Point mutation DNA Helicases Articles Cytochromes b Middle Aged Locus Control Region Molecular biology DNA Polymerase gamma Pedigree Mutagenesis Child Preschool biology.protein Female |
| Zdroj: | Nucleic acids research |
| ISSN: | 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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