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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot\u2013Marie\u2013Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT.<\/jats:p>","DOI":"10.3390\/ijms27167481","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:31:59Z","timestamp":1787304719000},"page":"7481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI"],"prefix":"10.3390","volume":"27","author":[{"given":"Nancy","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6346-4699","authenticated-orcid":false,"given":"Tristan N.","family":"Samuels","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Bioinformatics Solutions Inc., Waterloo, ON N2L 3K8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ridhwan","family":"Busari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8395-5290","authenticated-orcid":false,"given":"Zain","family":"Nasir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Girard","sequence":"additional","affiliation":[{"name":"School of Integrated Science, Sustainability, and Public Health, University of Illinois Springfield, Springfield, IL 62703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah M.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"School of Integrated Science, Sustainability, and Public Health, University of Illinois Springfield, Springfield, IL 62703, USA"}],"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 3K7, Canada"},{"name":"Children\u2019s Health Research Institute, London, ON N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1128\/MMBR.64.1.202-236.2000","article-title":"Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process","volume":"64","author":"Woese","year":"2000","journal-title":"Microbiol. 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