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

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.

doi:10.1086/504303

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

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. +2 more·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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Of the handful of heterozygous mutations identified in POLG2, G451E and R369G are linked to PEO.
“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
Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G.
“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
G451E homodimers fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.
“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

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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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