Characterization of disease-causing HARS mutations
Abstract
Aminoacyl-tRNA synthetases ligate amino acids to their cognate tRNAs during protein synthesis. Mutations in the catalytic domain of histidyl-tRNA synthetase (HARS) lead to an incurable neurodegenerative disease Charcot Marie Tooth Disease Type 2W (CMT2W), with the molecular basis of many disease-causing mutations unknown. I generated a yeast model for CMT2W-causing HARS mutations V133F, V155G, Y330C, and S356N. All human HARS variants complemented genomic deletion of yeast ortholog histidyl tRNA synthetase 1 (HTS1) but with reduced growth. HARS V155G and S356N lead to global insoluble protein accumulation, with their growth defect and perturbed proteome rescued by histidine supplementation. HARS V133F and Y330C decreased HARS abundance and histidine supplementation further reduced viability, indicating histidine toxicity. As histidine is in clinical trials for treating patients with HARS mutations, our data will inform treatment options for CMT patients, where histidine supplementation may either have a toxic or compensating effect depending on the nature of the causative HARS variant.