Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Human Molecular Genetics |
| Vol/bind | 31 |
| Udgave nummer | 4 |
| Sider (fra-til) | 523-534 |
| ISSN | 0964-6906 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Authors acknowledge the support fromthe UKNational Institute for Health Research (NIHR) Biomedical Research Centre (BRC) for Ageing and Age-Related Disease award to the Newcastle Upon Tyne Hospitals NHS Foundation Trust, the Lily Foundation, the Pathology Society and the UK NHS Specialist Commissioners which funds the Rare Mitochondrial Disorders of Adults and Children Diagnostic Service in Newcastle upon Tyne. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Conflicts of interest statement. The authors declare no conflicts of interest. Natural Science Foundation of China (31670801, 31822015, 81870896 to X.L.Z.);Wellcome Centre for Mitochondrial Research (203105/Z/16/Z to R.W.T.); 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 to R.H.); 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) and Lily Foundation and the Evelyn Trust.
Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved.
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