The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Mutant POLG2 Disrupts DNA Polymerase γ Subunits and Causes Progressive External Ophthalmoplegia
Open accessAbstract
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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In the citing paper
“Of the handful of heterozygous mutations identified in POLG2, G451E (Longley et al., 2006) and R369G (Craig et al., 2012; Young et al., 2011) are linked to PEO.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2006
In the citing paper
“Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G (Craig et al., 2012; Longley et al., 2006; Young et al., 2011).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2006
In the citing paper
“G451E homodimers also fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Longley et al., 2006
Citations
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POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion
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Research works printed but not linked: 1
- Hudson G, Deschauer M, Taylor RW, Hanna MG, Fialho D, Schaefer AM, He L-P, Blakely E, Turnbull DM, Chinnery PF. POLG1, C10ORF2 and ANT1 mutations are uncommon in sporadic PEO with multiple mtDNA deletions. Neurology (in press)
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Gorman, G. S., Chinnery, P. F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D. R., Zeviani, M., & Turnbull, D. M. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.80 · Cited by 1,650
Mitochondrial Dynamics in Mammalian Health and Disease
Liesa, M., Palacín, M., & Zorzano, A. (2009) · Physiological Reviews · doi:10.1152/physrev.00030.2008 · Cited by 953
DNA replication and transcription in mammalian mitochondria.
Falkenberg, M., Larsson, N., & Gustafsson, C. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.060305.152028 · Cited by 686
Mitochondrial optic neuropathies—Disease mechanisms and therapeutic strategies
Yu-Wai-Man, P., Griffiths, P. G., & Chinnery, P. F. (2011) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.11.002 · Cited by 633
Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R., Anselm, I., Cohen, B. H., Falk, M. J., Greene, C., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2014.177 · Cited by 607
Metadata
- Authors
- Longley, M. J., Clark, S., Yu Wai Man, C., Hudson, G., Durham, S. E., Taylor, R. W., Nightingale, S., Turnbull, D. M., Copeland, W. C., & Chinnery, P. F.
- Affiliations
- National Institutes of Health (US)
- Newcastle University (GB)
- Royal Shrewsbury Hospital (GB)
- Corresponding author
- Chinnery, Patrick F.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 78
- Issue
- 6
- Pages
- 1026-1034
- ISSN
- 0002-9297 (ISSN-L)
- OpenAlex
- W2029707526
- Cited by
- 248
- References
- 25
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 9 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 16 · 2013: 14 · 2012: 13
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- United Mitochondrial Disease Foundation
- Wellcome Trust (074454)
- European Commission
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- POLG2, DNA polymerase gamma, chronic progressive external ophthalmoplegia, mitochondrial DNA deletions, cytochrome c oxidase deficiency, mitochondrial disease, replication fork stalling, subunit interactions, DNA binding
- MeSH terms
- DNA Polymerase gamma, Amino Acid Sequence, Electron Transport Complex IV, DNA, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Enzyme Inhibitors, Ethylmaleimide, Female, Heterozygote, Humans, Middle Aged, Molecular Sequence Data, Mutation, Ophthalmoplegia, Chronic Progressive External, Age of Onset, Muscle, Skeletal, Muscle Fibers, Skeletal, Dimerization, Nucleic Acid Synthesis Inhibitors, Catalytic Domain, Protein Subunits
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