Zheng Wen-Qiang, Pedersen Signe Vandal, Thompson Kyle, Bellacchio Emanuele, French Courtney E, Munro Benjamin, Pearson Toni S, Vogt Julie, Diodato Daria, Diemer Tue, Ernst Anja, Horvath Rita, Chitre Manali, Ek Jakob, Wibrand Flemming, Grange Dorothy K, Raymond Lucy, Zhou Xiao-Long, Taylor Robert W, Ostergaard Elsebet
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Hum Mol Genet. 2022 Feb 21;31(4):523-534. doi: 10.1093/hmg/ddab257.
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.
TARS2编码人类线粒体苏氨酰tRNA合成酶，该酶负责在线粒体翻译过程中生成线粒体苏氨酰 - tRNAThr并清除错误加载的丝氨酰 - tRNAThr。迄今为止，已在一对兄弟姐妹和一名无关患者中报道了TARS2的致病变体，这些患者患有早发性线粒体脑病且肌肉中存在联合呼吸链酶缺乏症。我们在此报告另外五名与TARS2相关的线粒体疾病无关患者，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，我们记录了七个新的TARS2变体——一个无义变体和六个错义变体——基于群体频率、同源建模和功能研究，我们证明这些变体具有致病性且是疾病表现的病因，这些研究显示了致病变体对TARS2稳定性和/或功能的影响。
