ArticleHuman molecular genetics2011
Biochemical analysis of human POLG2 variants associated with mitochondrial disease.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 65 citations in OpenAlex.
- Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.Translational neurodegeneration · 2026Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.Cell death & disease · 2025Article
- Coordinated DNA polymerization by Polγ and the region of LonP1 regulated proteolysis.Nucleic acids research · 2024Article
- POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature.Cerebellum (London, England) · 2024Review
- Structural basis for DNA proofreading.Nature communications · 2023Article
- Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.Nucleic acids research · 2023Article
- Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using YeastInternational journal of molecular sciences · 2023Review
- Therapy Prospects for Mitochondrial DNA Maintenance Disorders.International journal of molecular sciences · 2021Review
- Rod bipolar cell dysfunction in POLG retinopathy.Documenta ophthalmologica. Advances in ophthalmology · 2021Article
- Mechanisms of replication and repair in mitochondrial DNA deletion formation.Nucleic acids research · 2020Review
- Consequences of compromised mitochondrial genome integrity.DNA repair · 2020Review
- Camptocormia as a Novel Phenotype in a HeterozygousDiagnostics (Basel, Switzerland) · 2020Article
- Roles of the mitochondrial replisome in mitochondrial DNA deletion formation.Genetics and molecular biology · 2020Article
- Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation.JAMA network open · 2019Article
- AJournal of clinical neurology (Seoul, Korea) · 2019Article
- An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2019Article
- Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases.BMC medical genetics · 2018Article
- Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome.PloS one · 2018Article
- Inherited mitochondrial genomic instability and chemical exposures.Toxicology · 2017Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Defects in mitochondrial DNA (mtDNA) maintenance comprise an expanding repertoire of polymorphic diseases caused, in part, by mutations in the genes encoding the p140 mtDNA polymerase (POLG), its p55 accessory subunit (POLG2) or the mtDNA helicase (C10orf2). In an exploration of nuclear genes for mtDNA maintenance linked to mitochondrial disease, eight heterozygous mutations (six novel) in POLG2 were identified in one control and eight patients with POLG-related mitochondrial disease that lacked POLG mutations. Of these eight mutations, we biochemically characterized seven variants [c.307G>A (G103S); c.457C>G (L153V); c.614C>G (P205R); c.1105A>G (R369G); c.1158T>G (D386E); c.1268C>A (S423Y); c.1423_1424delTT (L475DfsX2)] that were previously uncharacterized along with the wild-type protein and the G451E pathogenic variant. These seven mutations encode amino acid substitutions that map throughout the protein, including the p55 dimer interface and the C-terminal domain that interacts with the catalytic subunit. Recombinant proteins harboring these alterations were assessed for stimulation of processive DNA synthesis, binding to the p140 catalytic subunit, binding to dsDNA and self-dimerization. Whereas the G103S, L153V, D386E and S423Y proteins displayed wild-type behavior, the P205R and R369G p55 variants had reduced stimulation of processivity and decreased affinity for the catalytic subunit. Additionally, the L475DfsX2 variant, which possesses a C-terminal truncation, was unable to bind the p140 catalytic subunit, unable to bind dsDNA and formed aberrant oligomeric complexes. Our biochemical analysis helps explain the pathogenesis of POLG2 mutations in mitochondrial disease and emphasizes the need to quantitatively characterize the biochemical consequences of newly discovered mutations before classifying them as pathogenic.
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Registered trials
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