Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.

Charcot-Marie-Tooth disease (CMT) is a genetically diverse hereditary disorder that affects the motor and sensory nerves, impacting about 1 in 2500 people. It can be inherited through autosomal dominant (AD), autosomal recessive (AR), or X-linked genetic patterns. CMT2, one of the primary subtypes, is characterized by axonal degeneration and commonly presents with muscle weakness, atrophy, foot deformities, and sensory loss. Aminoacyl-tRNA synthetases (aaRSs) play an important role in the genetic underpinnings of CMT2, with more than 60 disease-causing alleles identified across eight different aaRSs, including alanyl-, asparaginyl-, histidyl-, glycyl-, methionyl-, tryptophanyl-, seryl-, and tyrosyl-tRNA synthetases. Mutations in aaRS genes can lead to destabilization of the enzyme, reduced aminoacylation, and aberrant protein complex formation. Yeast as a simple organism provides a robust model system to study the pathogenic effects of aaRS CMT mutations. In this review, we discuss the advantages and limitations of the yeast model systems for CMT2-causative mutations in aaRS.