A missense, loss-of-function variant in a patient with proximal-predominant motor neuropathy.

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 (, , , , and ) 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 of 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 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in and the yeast ortholog ; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in .