Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
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...
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Springer Nature
2023-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216775 |
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| author | 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 de Moura 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 |
| author_facet | 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 de Moura 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 |
| author_sort | Direnis Erdinc |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c9e7e4ced0784d4394725c67d2a116f4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-c9e7e4ced0784d4394725c67d2a116f42024-11-10T12:37:44ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-04-0115512110.15252/emmm.202216775Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stabilityDirenis Erdinc0Alejandro Rodríguez‐Luis1Mahmoud R Fassad2Sarah Mackenzie3Christopher M Watson4Sebastian Valenzuela5Xie Xie6Katja E Menger7Kate Sergeant8Kate Craig9Sila Hopton10Gavin Falkous11Genomics England Research ConsortiumJoanna Poulton12Hector Garcia‐Moreno13Paola Giunti14Carlos A de Moura Aschoff15Jonas A Morales Saute16Amelia J Kirby17Camilo Toro18Lynne Wolfe19Danica Novacic20Lior Greenbaum21Aviva Eliyahu22Ortal Barel23Yair Anikster24Robert McFarland25Gráinne S Gorman26Andrew M Schaefer27Claes M Gustafsson28Robert W Taylor29Maria Falkenberg30Thomas J Nicholls31Department of Medical Biochemistry and Cell Biology, University of GothenburgWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityThe Newcastle Upon Tyne Hospitals NHS Foundation TrustNorth East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University HospitalDepartment of Medical Biochemistry and Cell Biology, University of GothenburgDepartment of Medical Biochemistry and Cell Biology, University of GothenburgWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation TrustWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityNuffield Department of Women's & Reproductive Health, The Women's Centre, University of OxfordDepartment of Clinical and Movement Neurosciences, Ataxia Centre, UCL Queen Square Institute of NeurologyDepartment of Clinical and Movement Neurosciences, Ataxia Centre, UCL Queen Square Institute of NeurologyMedical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA)Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA)Department of Pediatrics, Wake Forest School of MedicineUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of HealthUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of HealthUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of HealthThe Danek Gertner Institute of Human Genetics, Sheba Medical CenterThe Danek Gertner Institute of Human Genetics, Sheba Medical CenterGenomics Unit, The Center for Cancer Research, Sheba Medical CenterSackler Faculty of Medicine, Tel Aviv UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityDepartment of Medical Biochemistry and Cell Biology, University of GothenburgWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityDepartment of Medical Biochemistry and Cell Biology, University of GothenburgWellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle UniversityAbstract 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.https://doi.org/10.15252/emmm.202216775Bloom syndromemitochondrial diseasemtDNATOP3A |
| spellingShingle | 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 de Moura 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 Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability EMBO Molecular Medicine Bloom syndrome mitochondrial disease mtDNA TOP3A |
| title | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| title_full | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| title_fullStr | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| title_full_unstemmed | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| title_short | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| title_sort | pathological variants in top3a cause distinct disorders of mitochondrial and nuclear genome stability |
| topic | Bloom syndrome mitochondrial disease mtDNA TOP3A |
| url | https://doi.org/10.15252/emmm.202216775 |
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