Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
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DOI：
10.15252/emmm.202216775
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发表时间：
2023-05-08
影响因子：
11.1
通讯作者：
Nicholls, Thomas J.
中科院分区：
文献类型：
--
作者：
Erdinc, Direnis;Rodriguez-Luis, Alejandro;Fassad, Mahmoud R.;Mackenzie, Sarah;Watson, Christopher M.;Valenzuela, Sebastian;Xie, Xie;Menger, Katja E.;Sergeant, Kate;Craig, Kate;Hopton, Sila;Falkous, Gavin;Poulton, Joanna;Garcia-Moreno, Hector;Giunti, Paola;Aschoff, Carlos A. de Moura;Saute, Jonas A. Morales;Kirby, Amelia J.;Toro, Camilo;Wolfe, Lynne;Novacic, Danica;Greenbaum, Lior;Eliyahu, Aviva;Barel, Ortal;Anikster, Yair;McFarland, Robert;Gorman, Grainne S.;Schaefer, Andrew M.;Gustafsson, Claes M.;Taylor, Robert W.;Falkenberg, Maria;Nicholls, Thomas J.
拓扑异构酶3α（Topoisomerase 3α，TOP3A）是一种消除扭转应变和DNA分子之间相互连接的酶。TOP3A定位于细胞核和线粒体，两种亚型分别在DNA重组和复制中发挥专门作用。TOP3A中的致病性变体可引起类似于Bloom综合征的病症，其由BLM中的双等位基因致病性变体引起，编码TOP3A的核结合配偶体。在这项工作中，我们描述了来自9个家庭的11名患有由双等位基因TOP3A基因变异引起的成人发病线粒体疾病的个体。大多数患者具有一致的临床表型，其特征为双侧上睑下垂、眼肌麻痹、肌病和轴突感觉运动神经病。我们对来自线粒体疾病和Bloom样综合征患者的TOP3A变体对mtDNA维持和酶功能不同方面的影响进行了全面的表征。基于这些结果，我们提出了一个模型，其中TOP3A催化缺陷的总体严重程度决定了临床结果，较轻的变异导致成人发病的线粒体疾病，较严重的变异导致儿童期线粒体功能障碍的布卢姆样综合征。我们报告了由拓扑异构酶TOP3A中的病理变异引起的成人发病线粒体疾病的病例，拓扑异构酶TOP3A定位于线粒体和细胞核。我们认为，不同的变异导致不同的疾病结果与线粒体或核形式的酶。
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. We report cases of adult‐onset mitochondrial disease caused by pathological variants in the topoisomerase TOP3A, which localises both to mitochondria and nucleus. We propose that different variants result in different disease outcomes related to the mitochondrial or nuclear forms of the enzyme.
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影响因子：
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