期刊
HUMAN MOLECULAR GENETICS
卷 31, 期 4, 页码 523-534出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab257
关键词
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资金
- Natural Science Foundation of China [31670801, 31822015, 81870896]
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease [MR/S005021/1]
- Mitochondrial Disease Patient Cohort (UK) [G0800674]
- European Research Council [309548]
- Wellcome Investigator Award [109915/Z/15/Z]
- Medical Research Council (UK) [MR/N025431/1]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- Newton Fund (UK/Turkey) [MR/N027302/1]
- Lily Foundation
- Evelyn Trust
- Wellcome Trust [109915/Z/15/Z] Funding Source: Wellcome Trust
TARS2 gene encodes a mitochondrial enzyme crucial for mitochondrial protein synthesis, and its pathogenic variants can lead to mitochondrial diseases. New cases reported in this study have expanded the clinical spectrum of TARS2-related mitochondrial diseases, demonstrating the pathogenic nature of these variants.
TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNA(Thr) and clearing mischarged Ser-tRNA(Thr) 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.
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