Cited by 248Mitochondrial Function and PathologyDNA Repair MechanismsMetabolism and Genetic Disorders

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Mutant POLG2 Disrupts DNA Polymerase γ Subunits and Causes Progressive External Ophthalmoplegia

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Longley, Matthew J., Clark, Susanna, Yu Wai Man, Cynthia, Hudson, Gavin, Durham, Steve E., Taylor, Robert W., Nightingale, Simon, Turnbull, Douglass M., Copeland, William C., Chinnery, Patrick F.·2006·The American Journal of Human Genetics

DOI 10.1086/504303

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Abstract

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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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: Longley, Matthew J.
Hudson, Gavin
Taylor, Robert W.
Turnbull, Douglass M.
Copeland, William C.
Chinnery, Patrick F.
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)
DOI: 10.1086/504303
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2605 d)
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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Mutant POLG2 Disrupts DNA Polymerase γ Subunits and Causes Progressive External Ophthalmoplegia

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