A missense, loss-of-functionYARS1variant in a patient with proximal-predominant motor neuropathy

Abstract

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 (AARS1,GARS1,HARS1,WARS1, andYARS1) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot–Marie–Tooth disease (CMT). Missense variants in the catalytic domain ofYARS1were 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 ofYARS1(p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenicYARS1variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled inYARS1and the yeast orthologTYS1; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certainYARS1variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions inYARS1.