Erdinc, Direnis;
Rodríguez-Luis, Alejandro;
Fassad, Mahmoud R;
Mackenzie, Sarah;
Watson, Christopher M;
Valenzuela, Sebastian;
Xie, Xie;
... Nicholls, Thomas J; + view all
(2023)
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
EMBO Molecular Medicine
, Article e16775. 10.15252/emmm.202216775.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.202216775 |
| Publisher version: | https://doi.org/10.15252/emmm.202216775 |
| Language: | English |
| Additional information: | © 2023 The Authors. Published under the terms of the CC BY 4.0 license (http://creativecommons.org/licenses/by/4.0/). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Bloom syndrome, TOP3A, mitochondrial disease, mtDNA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10167789 |
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