ArticleEMBO molecular medicine2023
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
Article in EMBO molecular medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Mitochondrial dysfunction drives ZBP1-mediated PANoptosis to increase the susceptibility of heart failure with preserved ejection fraction-associated atrial fibrillation.Journal of advanced research · 2026Article
- Brain age gap as biomarker linking cardiovascular diseases genetic susceptibility and causality.iScience · 2026Article
- The Roles of Topoisomerases in Transcriptional Regulation.International journal of molecular sciences · 2026Review
- Identification of aFrontiers in pharmacology · 2026Article
- Proteolytic cleavage activates the mitochondrial isoform of TOP3A.Nucleic acids research · 2025Article
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Ophthalmological signs and sensorimotor evaluation in mitochondrial chronic progressive external ophthalmoplegia: a multidisciplinary prospective study.BMC ophthalmology · 2025Article
- Topoisomerase IIIα controls alternative lengthening of telomeres.Cell reports · 2025Article
- Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study.Clinical genetics · 2025Article
- MRE11-independent effects of Mirin on mitochondrial DNA integrity and cellular immune responses.Molecular biology of the cell · 2025Article
- Mitochondrial DNA depletion syndrome and its cardiac complication.Frontiers in cardiovascular medicine · 2025Review
- Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.The Biochemical journal · 2024Review
- Predicting prostate adenocarcinoma patients' survival and immune signature: a novel risk model based on telomere-related genes.Discover oncology · 2024Article
- Mitochondrial DNA release and sensing in innate immune responses.Human molecular genetics · 2024Review
- Variation of Structure and Cellular Functions of Type IA Topoisomerases across the Tree of Life.Cells · 2024Review
- Mitochondrial Chronic Progressive External Ophthalmoplegia.Brain sciences · 2024Review
- TOP3A coupling with replication forks and repair of TOP3A cleavage complexes.Cell cycle (Georgetown, Tex.) · 2024Review
- Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.International journal of molecular sciences · 2023Review
- Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.EMBO molecular medicine · 2023Article
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Authors and funding
33 authors at 14 institutions in 5 countries.
Funding
Abstract
Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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