EMBO Molecular Medicine (May 2023)
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- Direnis Erdinc,
- Alejandro Rodríguez‐Luis,
- Mahmoud R Fassad,
- Sarah Mackenzie,
- Christopher M Watson,
- Sebastian Valenzuela,
- Xie Xie,
- Katja E Menger,
- Kate Sergeant,
- Kate Craig,
- Sila Hopton,
- Gavin Falkous,
- Genomics England Research Consortium,
- Joanna Poulton,
- Hector Garcia‐Moreno,
- Paola Giunti,
- Carlos A deMoura Aschoff,
- Jonas A Morales Saute,
- Amelia J Kirby,
- Camilo Toro,
- Lynne Wolfe,
- Danica Novacic,
- Lior Greenbaum,
- Aviva Eliyahu,
- Ortal Barel,
- Yair Anikster,
- Robert McFarland,
- Gráinne S Gorman,
- Andrew M Schaefer,
- Claes M Gustafsson,
- Robert W Taylor,
- Maria Falkenberg,
- Thomas J Nicholls
Affiliations
- Direnis Erdinc
- Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden
- Alejandro Rodríguez‐Luis
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Mahmoud R Fassad
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Sarah Mackenzie
- The Newcastle Upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK
- Christopher M Watson
- North East and Yorkshire Genomic Laboratory Hub, Central Lab St. James's University Hospital Leeds UK
- Sebastian Valenzuela
- Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden
- Xie Xie
- Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden
- Katja E Menger
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Kate Sergeant
- Oxford Genetics Laboratories Oxford University Hospitals NHS Foundation Trust Oxford UK
- Kate Craig
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Sila Hopton
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Gavin Falkous
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Genomics England Research Consortium
- Joanna Poulton
- Nuffield Department of Women's & Reproductive Health, The Women's Centre University of Oxford Oxford UK
- Hector Garcia‐Moreno
- Department of Clinical and Movement Neurosciences, Ataxia Centre UCL Queen Square Institute of Neurology London UK
- Paola Giunti
- Department of Clinical and Movement Neurosciences, Ataxia Centre UCL Queen Square Institute of Neurology London UK
- Carlos A deMoura Aschoff
- Medical Genetics Service Hospital de Clínicas de Porto Alegre (HCPA) Porto Alegre Brazil
- Jonas A Morales Saute
- Medical Genetics Service Hospital de Clínicas de Porto Alegre (HCPA) Porto Alegre Brazil
- Amelia J Kirby
- Department of Pediatrics Wake Forest School of Medicine Winston‐Salem NC USA
- Camilo Toro
- Undiagnosed Diseases Program National Human Genome Research Institute, National Institutes of Health Bethesda MD USA
- Lynne Wolfe
- Undiagnosed Diseases Program National Human Genome Research Institute, National Institutes of Health Bethesda MD USA
- Danica Novacic
- Undiagnosed Diseases Program National Human Genome Research Institute, National Institutes of Health Bethesda MD USA
- Lior Greenbaum
- The Danek Gertner Institute of Human Genetics Sheba Medical Center Tel Hashomer Israel
- Aviva Eliyahu
- The Danek Gertner Institute of Human Genetics Sheba Medical Center Tel Hashomer Israel
- Ortal Barel
- Genomics Unit The Center for Cancer Research, Sheba Medical Center Tel Hashomer Israel
- Yair Anikster
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Robert McFarland
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Gráinne S Gorman
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Andrew M Schaefer
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Claes M Gustafsson
- Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden
- Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Maria Falkenberg
- Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden
- Thomas J Nicholls
- Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- DOI
- https://doi.org/10.15252/emmm.202216775
- Journal volume & issue
-
Vol. 15,
no. 5
pp. n/a – n/a
Abstract
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.
Keywords