A missense, loss-of-function YARS1 variant 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, 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.

Figure 1.

A loss-of-function YARS1 variant in a patient with proximal-prominent neuropathy. (A–C) Clinical findings noted on the patient's physical exam, including atrophy of the distal upper extremities and hand muscles (A) and finger extensor weakness demonstrated by finger drop (B,C). (D) Pedigree of the proband's (arrow) family. Genotypes at p.Asp308 YARS1 are indicated below each individual (??/?? indicates an unknown genotype). Filled objects indicate that the individual is affected, whereas unfilled objects indicate that the individual is unaffected. A slash through an individual indicates that they are deceased. (E) YARS1 protein sequence alignment, including six evolutionarily diverse species centered around the affected p.Asp308 residue (indicated in red). (F) Haploid yeast lacking endogenous TYS1 were transformed with a LEU2-bearing pRS315 vector to express wild type, p.Gly41Arg, p.Asp308Tyr, or p.Pro167Thr TYS1, or with a vector containing no TYS1 insert (“No Insert”). Resultant yeast cultures were plated undiluted or diluted (1:10, 1:100, or 1:1000) on solid media without leucine or uracil (−leu −ura) (see Supplemental Fig. 1A) or on solid media containing 5-FOA and grown at 30°C. Replicates A and B indicate two separate colonies from a single transformation. Image shown is representative of two independent transformations using two different plasmid DNA preparations (p.Asp308Tyr TYS1 total n = 8). (G) Haploid yeast lacking endogenous TYS1 were transformed with a LEU2-bearing pAG425-GPD vector to express wild-type TYS1, p.Asp308Tyr TYS1, wild-type YARS1, or p.Asp308Tyr YARS1, or with a vector containing no TYS1 insert (“No Insert”). Resultant yeast cultures were plated undiluted or diluted (1:10, 1:100, or 1:1000) on solid media without leucine or uracil (−leu −ura) (see Supplemental Fig. 1B) or on solid media containing 5-FOA and grown at 30°C. Replicates A and B indicate colonies from transformations using two different plasmid DNA preparations. Image shown is representative of two independent transformations using two different plasmid DNA preparations (p.Asp308Tyr YARS1 total n = 6).