期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 78, 期 6, 页码 1026-1034出版社
UNIV CHICAGO PRESS
DOI: 10.1086/504303
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资金
- Intramural NIH HHS Funding Source: Medline
- Wellcome Trust [074454] Funding Source: Medline
DNA polymerase gamma (pol gamma) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G -> A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol gamma, that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)-deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.
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