TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

中文翻译：

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阐明与 TARS2 相关线粒体疾病相关的分子机制

TARS2 编码人线粒体苏氨酰 tRNA 合成酶，负责在线粒体翻译过程中产生线粒体 Thr-tRNAThr 并清除错误充电的 Ser-tRNAThr。迄今为止，已在一对兄弟姐妹和一名患有早发性线粒体脑肌病和肌肉呼吸链酶缺乏症的无关患者中报道了 TARS2 的致病变异。我们在这里报告了另外五名患有 TARS2 相关线粒体疾病的无关患者，将临床表型扩展到还包括癫痫、肌张力障碍、多汗症和严重听力障碍。此外，我们记录了七种新的 TARS2 变体——一个无义变体和六个错义变体——我们根据人群频率证明它们是致病的并且是疾病表现的因果关系，