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

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition. These include central and peripheral nervous system impairment, heart and liver disease, and deafness. In patients, it can lead to immune-hematological abnormalities like hypogammaglobulinemia, B cell lymphopenia, and impaired vaccine responses. In zebrafish, loss-of-function alleles of kars1 lead to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key disease phenotypes of patients [1,2]. In yeast mutants, most KARS1 variants cause a growth defect of variable severity in both cytosolic and mitochondrial isoforms, and the detrimental effects of some variants can be partially rescued by lysine supplementation [3].

In conclusion, KARS1 plays a crucial role in multiple physiological processes through its involvement in t-RNA synthesis of lysine. The study of KARS1 using genetic models such as zebrafish and yeast mutants has provided insights into the pathogenesis of KARS-related diseases, including neurological, immunological, and multi-system disorders, and also suggests potential therapeutic strategies like lysine supplementation.