A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations

Hum Mol Genet. 2023 Jun 19;32(13):2177-2191. doi: 10.1093/hmg/ddad054.


Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility that neuropathy-associated ARS variants exert a dominant-negative effect, reducing overall ARS activity below a threshold required for peripheral nerve function. To test such variants for dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase (AARS1) mutations with wild-type human AARS1. We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth. This suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.

Publication types

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

MeSH terms

  • Alanine-tRNA Ligase* / genetics
  • Amino Acyl-tRNA Synthetases* / genetics
  • Humans
  • Mutation
  • Peripheral Nerves / metabolism
  • Peripheral Nervous System Diseases* / pathology


  • Alanine-tRNA Ligase
  • Amino Acyl-tRNA Synthetases