A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy

Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7):a006246. doi: 10.1101/mcs.a006246. Print 2022 Dec.


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, and YARS1) 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 YARS1 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 YARS1 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic YARS1 variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in YARS1 and the yeast ortholog TYS1; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain YARS1 variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in YARS1.

Keywords: areflexia of upper limbs; generalized limb muscle atrophy; lower limb muscle weakness; upper limb muscle weakness.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acyl-tRNA Synthetases* / genetics
  • Charcot-Marie-Tooth Disease* / genetics
  • Heterozygote
  • Humans
  • Mutation
  • Mutation, Missense / genetics
  • Saccharomyces cerevisiae


  • Amino Acyl-tRNA Synthetases