ArticleBiochimica et biophysica acta2014
Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.
Article in Biochimica et biophysica acta, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 48 citations in OpenAlex.
- POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.Molecular genetics and metabolism reports · 2026Article
- Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.Scientific reports · 2026Article
- Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.Nature communications · 2025Article
- TheGenes · 2025Article
- Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.Neurology. Genetics · 2024Article
- Epidemiology and natural history of POLG disease in Norway: a nationwide cohort study.Annals of clinical and translational neurology · 2024Article
- Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions.Molecular genetics & genomic medicine · 2022Article
- Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ.Mitochondrion · 2021Article
- Rod bipolar cell dysfunction in POLG retinopathy.Documenta ophthalmologica. Advances in ophthalmology · 2021Article
- POLG1-Related Epilepsy: Review of Diagnostic and Therapeutic Findings.Brain sciences · 2020Review
- Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response.The Enzymes · 2019Review
- Inherited mitochondrial genomic instability and chemical exposures.Toxicology · 2017Review
- Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database.BBA clinical · 2017Article
- Synergistic Effects of theThe Journal of biological chemistry · 2017Article
- Structure, function and evolution of the animal mitochondrial replicative DNA helicase.Critical reviews in biochemistry and molecular biology · 2016Review
- Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease.Human genetics · 2015Article
- Evolution of the metazoan mitochondrial replicase.Genome biology and evolution · 2015Article
- Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.Mitochondrion · 2015Article
- Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms.Frontiers in genetics · 2015Article
- DNA polymerase γ and disease: what we have learned from yeast.Frontiers in genetics · 2015Review
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Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
Abstract
We establish the genotype-phenotype correlations for the complete spectrum of POLG syndromes by refining our previously described protocol for mapping pathogenic mutations in the human POLG gene to functional clusters in the catalytic core of the mitochondrial replicase, Pol γ (1). We assigned 136 mutations to five clusters and identify segments of primary sequence that can be used to delimit the boundaries of each cluster. We report that compound heterozygotes with two mutations from different clusters manifested more severe, earlier-onset POLG syndromes, whereas two mutations from the same cluster are less common and generally are associated with less severe, later onset POLG syndromes. We also show that specific cluster combinations are more severe than others and have a higher likelihood to manifest at an earlier age. Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders. We propose that such a prediction tool would be useful for routine diagnostics for mitochondrial disorders. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
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