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

Lookup NU author(s): Dr Mahmoud Fassad, Dr Katja MengerORCiD, Sila Hopton, Gavin Falkous, Professor Bobby McFarlandORCiD, Professor Grainne Gorman, Professor Robert Taylor, Dr Thomas NichollsORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Authors. Published under the terms of the CC BY 4.0 license.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.

Publication metadata

Author(s): Erdinc D, Rodriguez-Luis A, Fassad MR, Mackenzie S, Watson CM, Valenzuela S, Xie X, Menger KE, Sergeant K, Craig K, Hopton S, Falkous G, Poulton J, Garcia-Moreno H, Giunti P, de Moura Aschoff CA, Morales Saute JA, Kirby AJ, Toro C, Wolfe L, Novacic D, Greenbaum L, Eliyahu A, Barel O, Anikster Y, McFarland R, Gorman GS, Schaefer AM, Gustafsson CM, Taylor RW, Falkenberg M, Nicholls TJ

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2023

Volume: 15

Issue: 5

Print publication date: 08/05/2023

Online publication date: 14/03/2023

Acceptance date: 14/03/2023

Date deposited: 19/06/2023

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: John Wiley and Sons Inc


DOI: 10.15252/emmm.202216775


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