KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase involved in multiple physiological mechanisms such as angiogenesis, post-translational modifications, translation initiation, autophagy, and mitochondrial function [1,3]. There are two different KARS1 isoforms exerting functional effects in cytosol and mitochondria [3].

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition. Patients often present with central and peripheral nervous system impairment, heart and liver disease, deafness, and immune-hematological abnormalities [1]. In zebrafish, loss-of-function alleles of kars1 lead to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients, and inhibition of p53 rescued several defects of kars1-/-knockouts [2]. In yeast mutants, most KARS1 variants led to a growth defect of variable severity on both cytosolic and mitochondrial isoforms, and the detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation [3].

In conclusion, KARS1 is crucial for various physiological mechanisms through its role as a lysyl-tRNA synthetase. Studies using zebrafish and yeast models have provided insights into the phenotypes associated with KARS1 dysfunction, such as neurodevelopmental disorders, and potential therapeutic approaches like lysine supplementation [1,2,3].