Browse by author
Lookup NU author(s): Dr Steve Durham, Professor Robert Taylor, Emeritus Professor Doug Turnbull, Professor Patrick Chinnery
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
DNA polymerase γ (pol γ) 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 γ (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 γ, 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. © 2006 by The American Society of Human Genetics. All rights reserved.
Author(s): Longley MJ, Clark S, Man CYW, Hudson G, Durham SE, Taylor RW, Nightingale S, Turnbull DM, Copeland WC, Chinnery PF
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2006
Volume: 78
Issue: 6
Pages: 1026-1034
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1086/504303
DOI: 10.1086/504303
PubMed id: 16685652
Altmetrics provided by Altmetric
