Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

EMBO Molecular Medicine · 32 authors, 22 centres

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TL;DR

This study characterizes pathological variants in the dual-localized TOP3A gene, showing that different types of genetic errors lead to distinct human disorders: severe loss-of-function variants cause a childhood Bloom syndrome-like disorder, while variants with moderate functional impairment cause adult-onset mitochondrial disease.

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The study investigates pathological variants in the TOP3A gene, which encodes an enzyme localizing to both mitochondria and the nucleus. Variants causing severe loss of enzymatic activity are associated with a childhood Bloom syndrome-like disorder, whereas variants causing moderate impairment are linked to adult-onset mitochondrial disease, often presenting with progressive external ophthalmoplegia. MtDNA analysis in patients revealed abundant major arc rearrangements, consistent with a model where impaired TOP3A activity leads to replication stalling and deletion formation.

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other

SPECIALTY

neurology

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ORIGINAL PAPER

PMC10165364

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

EMBO Molecular Medicine

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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: Bloom syndrome, mitochondrial disease, mtDNA, TOP3A Subject Categories: Genetics, Gene Therapy & Genetic Disease; Organelles

CITATION EXPORT

Direnis Erdinc, Alejandro Rodríguez‐Luis, Mahmoud R Fassad et al.. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability. EMBO Molecular Medicine. (2023). https://doi.org/10.15252/emmm.202216775

AUTHORS

32 · 22 CENTRES

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, 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

1 Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden
2 Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
3 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
4 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
5 The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
6 North East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University Hospital, Leeds, UK
7 Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, UK
8 Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
9 NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
10 Nuffield Department of Women's & Reproductive Health, The Women's Centre, University of Oxford, Oxford, UK
11 Department of Clinical and Movement Neurosciences, Ataxia Centre, UCL Queen Square Institute of Neurology, London, UK
12 Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
13 Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
14 Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
15 Department of Pediatrics, Wake Forest School of Medicine, Winston‐Salem, NC, USA
16 Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
17 The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
18 The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel
19 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
20 Genomics Unit, The Center for Cancer Research, Sheba Medical Center, Tel Hashomer, Israel
21 Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
22 Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden