{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:33:23Z","timestamp":1790649203683,"version":"4.1.0"},"reference-count":40,"publisher":"Cold Spring Harbor Laboratory","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"accepted":{"date-parts":[[2022,10,24]]},"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:p>Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (<jats:italic>AARS1<\/jats:italic>,<jats:italic>GARS1<\/jats:italic>,<jats:italic>HARS1<\/jats:italic>,<jats:italic>WARS1<\/jats:italic>, and<jats:italic>YARS1<\/jats:italic>) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot\u2013Marie\u2013Tooth disease (CMT). Missense variants in the catalytic domain of<jats:italic>YARS1<\/jats:italic>were previously linked to dominant intermediate CMT type C (DI-CMTC). Here, we report a patient with a missense variant of unknown significance predicted to modify residue 308 in the anticodon binding domain of<jats:italic>YARS1<\/jats:italic>(p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic<jats:italic>YARS1<\/jats:italic>variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in<jats:italic>YARS1<\/jats:italic>and the yeast ortholog<jats:italic>TYS1<\/jats:italic>; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain<jats:italic>YARS1<\/jats:italic>variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in<jats:italic>YARS1<\/jats:italic>.<\/jats:p>","DOI":"10.1101\/mcs.a006246","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T21:00:10Z","timestamp":1666990810000},"page":"a006246","source":"Crossref","is-referenced-by-count":4,"title":["A missense, loss-of-function<i>YARS1<\/i>variant in a patient with proximal-predominant motor neuropathy"],"prefix":"10.1101","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1126-2738","authenticated-orcid":false,"given":"Megan E.","family":"Forrest","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3072-0212","authenticated-orcid":false,"given":"Alayne 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