{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:29:06Z","timestamp":1792801746529,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015668","name":"Ontario Ministry of Research and Innovation","doi-asserted-by":"publisher","award":["ER-18-14-183"],"award-info":[{"award-number":["ER-18-14-183"]}],"id":[{"id":"10.13039\/501100015668","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rare Diseases: Models and Mechanism Network"},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["04776\u20132014"],"award-info":[{"award-number":["04776\u20132014"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aminoacyl-tRNA synthetases are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C and S356N in the HARS catalytic domain cause Charcot\u2013Marie\u2013Tooth disease type 2\u00a0W (CMT2W), while tRNA-binding domain mutation Y454S causes recessive Usher syndrome type IIIB. In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, resulted in reduced growth. We show mistranslation of histidine to glutamine and threonine in V155G and S356N but not Y330C mutants in yeast. Mistranslating V155G and S356N mutants lead to accumulation of insoluble proteins, which was rescued by histidine. Mutants V133F and Y330C showed the most significant growth defect and decreased HARS abundance in cells. Here, histidine supplementation led to insoluble protein aggregation and further reduced viability, indicating histidine toxicity associated with these mutants. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA. Our data will inform future treatment options for HARS patients, where histidine supplementation may either have a toxic or compensating effect depending on the nature of the causative HARS variant.<\/jats:p>","DOI":"10.1093\/hmg\/ddac239","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T08:34:04Z","timestamp":1664181244000},"page":"810-824","source":"Crossref","is-referenced-by-count":24,"title":["Histidine supplementation can escalate or rescue HARS deficiency in a Charcot\u2013Marie\u2013Tooth disease model"],"prefix":"10.1093","volume":"32","author":[{"given":"Yi","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosan","family":"Kenana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruun","family":"Beharry","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah D P","family":"Wilhelm","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Yuan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria M","family":"Siu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Duennwald","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-1667","authenticated-orcid":false,"given":"Ilka U","family":"Heinemann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, ON N6A 5C1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"2023022108301443800_","doi-asserted-by":"crossref","first-page":"e029240","DOI":"10.1136\/bmjopen-2019-029240","article-title":"Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study","volume":"9","author":"Theadom","year":"2019","journal-title":"BMJ Open"},{"key":"2023022108301443800_","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s11940-008-0011-3","article-title":"Charcot-Marie-Tooth disease","volume":"10","author":"Carter","year":"2008","journal-title":"Curr. 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