{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T07:17:49Z","timestamp":1785827869456,"version":"3.56.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31670801"],"award-info":[{"award-number":["31670801"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31822015"],"award-info":[{"award-number":["31822015"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870896"],"award-info":[{"award-number":["81870896"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Centre for Mitochondrial Research","award":["203105\/Z\/16\/Z"],"award-info":[{"award-number":["203105\/Z\/16\/Z"]}]},{"name":"Genomic Medicine in Neuromuscular Disease","award":["MR\/S005021\/1"],"award-info":[{"award-number":["MR\/S005021\/1"]}]},{"name":"Mitochondrial Disease Patient Cohort","award":["G0800674"],"award-info":[{"award-number":["G0800674"]}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["309548"],"award-info":[{"award-number":["309548"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Investigator Award","award":["109915\/Z\/15\/Z"],"award-info":[{"award-number":["109915\/Z\/15\/Z"]}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N025431\/1"],"award-info":[{"award-number":["MR\/N025431\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust Pathfinder Scheme","award":["201064\/Z\/16\/Z"],"award-info":[{"award-number":["201064\/Z\/16\/Z"]}]},{"DOI":"10.13039\/100010897","name":"Newton Fund","doi-asserted-by":"publisher","award":["MR\/N027302\/1"],"award-info":[{"award-number":["MR\/N027302\/1"]}],"id":[{"id":"10.13039\/100010897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lily Foundation and the Evelyn Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2014one nonsense variant and six missense variants\u2014that 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddab257","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T11:28:18Z","timestamp":1631100498000},"page":"523-534","source":"Crossref","is-referenced-by-count":23,"title":["Elucidating the molecular mechanisms associated with <i>TARS2<\/i>-related mitochondrial disease"],"prefix":"10.1093","volume":"31","author":[{"given":"Wen-Qiang","family":"Zheng","sequence":"first","affiliation":[{"name":"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"},{"name":"School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Signe Vandal","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Thompson","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Bellacchio","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome 00165, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney E","family":"French","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Munro","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni S","family":"Pearson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Vogt","sequence":"additional","affiliation":[{"name":"West Midlands Regional Genetics Service, Birmingham Women's and Children\u2019s NHS Foundation Trust, Birmingham Women\u2019s Hospital, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Diodato","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurodegenerative Disease Unit, Children Hospital Bambino Ges\u00f9, Rome 00165, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tue","family":"Diemer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Aalborg University Hospital, Aalborg 9000, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg 9000, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manali","family":"Chitre","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Ek","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flemming","family":"Wibrand","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy K","family":"Grange","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2652-3355","authenticated-orcid":false,"given":"Lucy","family":"Raymond","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Long","family":"Zhou","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W","family":"Taylor","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8047-063X","authenticated-orcid":false,"given":"Elsebet","family":"Ostergaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen 2100, Denmark"},{"name":"Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"2022022310593449800_ref1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1146\/annurev.biochem.69.1.617","article-title":"Aminoacyl-tRNA synthesis","volume":"69","author":"Ibba","year":"2000","journal-title":"Annu. Rev. Biochem."},{"key":"2022022310593449800_ref2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/0959-440X(95)80008-O","article-title":"Aminoacyl-tRNA synthetases","volume":"5","author":"Delarue","year":"1995","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2022022310593449800_ref3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1042\/EBC20170103","article-title":"Mitochondrial DNA transcription and translation: clinical syndromes","volume":"62","author":"Boczonadi","year":"2018","journal-title":"Essays Biochem."},{"key":"2022022310593449800_ref4","doi-asserted-by":"crossref","first-page":"787956","DOI":"10.1155\/2014\/787956","article-title":"The mitochondrial aminoacyl tRNA synthetases: genes and syndromes","volume":"2014","author":"Diodato","year":"2014","journal-title":"Int. J. Cell Biol."},{"key":"2022022310593449800_ref5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ymeth.2016.11.013","article-title":"Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations","volume":"113","author":"Oprescu","year":"2017","journal-title":"Methods"},{"key":"2022022310593449800_ref6","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ymgme.2013.01.010","article-title":"Mitochondrial aminoacyl-tRNA synthetases in human disease","volume":"108","author":"Konovalova","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"2022022310593449800_ref7","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1002\/humu.23277","article-title":"MiSynPat: an integrated knowledge base linking clinical, genetic, and structural data for disease-causing mutations in human mitochondrial aminoacyl-tRNA synthetases","volume":"38","author":"Moulinier","year":"2017","journal-title":"Hum. Mutat."},{"key":"2022022310593449800_ref8","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.molmed.2017.06.002","article-title":"Recent advances in mitochondrial aminoacyl-tRNA Synthetases and disease","volume":"23","author":"Sissler","year":"2017","journal-title":"Trends Mol. Med."},{"key":"2022022310593449800_ref9","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1074\/jbc.M115.700849","article-title":"A human disease-causing point mutation in mitochondrial threonyl-tRNA synthetase induces both structural and functional defects","volume":"291","author":"Wang","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2022022310593449800_ref10","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1002\/humu.22590","article-title":"VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies","volume":"35","author":"Diodato","year":"2014","journal-title":"Hum. Mutat."},{"key":"2022022310593449800_ref11","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.1021\/bi047527z","article-title":"Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS","volume":"44","author":"Bonnefond","year":"2005","journal-title":"Biochemistry"},{"key":"2022022310593449800_ref12","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12881-020-01149-0","article-title":"Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report","volume":"21","author":"Li","year":"2020","journal-title":"BMC Med. Genet."},{"key":"2022022310593449800_ref13","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"2022022310593449800_ref14","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2022022310593449800_ref15","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/nature15510","article-title":"CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase","volume":"526","author":"He","year":"2015","journal-title":"Nature"},{"key":"2022022310593449800_ref16","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1038\/s41431-018-0204-5","article-title":"A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course","volume":"26","author":"Gronborg","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"2022022310593449800_ref17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00134-019-05552-x","article-title":"Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children","volume":"45","author":"French","year":"2019","journal-title":"Intensive Care Med."},{"key":"2022022310593449800_ref18","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/prot.22488","article-title":"Improved prediction of protein side-chain conformations with SCWRL4","volume":"77","author":"Krivov","year":"2009","journal-title":"Proteins"},{"key":"2022022310593449800_ref19","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/mus.21541","article-title":"Limited diagnostic value of enzyme analysis in patients with mitochondrial tRNA mutations","volume":"41","author":"Wibrand","year":"2010","journal-title":"Muscle Nerve"},{"key":"2022022310593449800_ref20","doi-asserted-by":"crossref","first-page":"3643","DOI":"10.1093\/nar\/gky211","article-title":"A threonyl-tRNA synthetase-like protein has tRNA aminoacylation and editing activities","volume":"46","author":"Chen","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022022310593449800_ref21","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.ajhg.2016.08.014","article-title":"Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number","volume":"99","author":"Thompson","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"2022022310593449800_ref22","doi-asserted-by":"crossref","first-page":"8857","DOI":"10.1093\/nar\/gkr595","article-title":"Role of tRNA amino acid-accepting end in aminoacylation and its quality control","volume":"39","author":"Zhou","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2022022310593449800_ref23","doi-asserted-by":"crossref","first-page":"36608","DOI":"10.1074\/jbc.M806745200","article-title":"The CP2 domain of leucyl-tRNA synthetase is crucial for amino acid activation and post-transfer editing","volume":"283","author":"Zhou","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2022022310593449800_ref24","doi-asserted-by":"crossref","first-page":"34042","DOI":"10.1074\/jbc.M206584200","article-title":"A carboxyl-terminal PDZ-interacting domain of scavenger receptor B, type I is essential for cell surface expression in liver","volume":"277","author":"Silver","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2022022310593449800_ref25","doi-asserted-by":"crossref","first-page":"34755","DOI":"10.1074\/jbc.M413511200","article-title":"The C-terminal appended domain of human cytosolic leucyl-tRNA synthetase is indispensable in its interaction with arginyl-tRNA synthetase in the multi-tRNA synthetase complex","volume":"280","author":"Ling","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2022022310593449800_ref26","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/nar\/gkx1231","article-title":"Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria","volume":"46","author":"Hilander","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022022310593449800_ref27","doi-asserted-by":"crossref","first-page":"4662","DOI":"10.1093\/nar\/gky243","article-title":"A natural non-Watson-crick base pair in human mitochondrial tRNAThr causes structural and functional susceptibility to local mutations","volume":"46","author":"Wang","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022022310593449800_ref28","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1093\/nar\/gkaa093","article-title":"Molecular basis for t6A modification in human mitochondria","volume":"48","author":"Zhou","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab257\/40672029\/ddab257.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/4\/523\/42579544\/ddab257.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/4\/523\/42579544\/ddab257.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:48:45Z","timestamp":1645620525000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/4\/523\/6367975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,11]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,9,11]]},"published-print":{"date-parts":[[2022,2,21]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab257","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,2,15]]},"published":{"date-parts":[[2021,9,11]]}}}