Gars1-flox Mouse

GARS1, encoding glycyl-tRNA synthetase, is a key gene in the aminoacyl-tRNA synthetase family, playing a crucial role in protein synthesis by catalyzing the attachment of glycine to its cognate tRNA [3]. It is associated with tRNA-related pathways [1].

Pathogenic variants of GARS1 can cause various neuromuscular disorders. For example, in a cross-sectional study of 12 patients with the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1, it was found that the patients presented with a distal hereditary motor neuropathy (dHMN) phenotype with "split hand" and sensory disturbances [2]. Functional studies of two novel missense variants modifying amino-acid position 336 in the catalytic domain of GARS1, identified in patients with infantile spinal muscular atrophy (iSMA) and Charcot-Marie-Tooth disease type 2D (CMT2D), suggested a loss-of-function effect [4]. Also, a novel GARS1 mutation (c.997G>C, p.E333Q) was identified in a Chinese family with infantile-onset CMT2D/dSMA-V, expanding the mutational spectrum of GARS1-related disorders [5]. In addition, GARS1 is highly expressed across cancers, especially in bladder urothelial carcinoma (BLCA), where its overexpression promotes cell proliferation, metastasis, and inhibits apoptosis, and is correlated with poor survival and specific immune infiltration [1,3].

In conclusion, GARS1 is essential for protein synthesis through its role in glycyl-tRNA formation. Its dysfunction, caused by pathogenic variants, is linked to neuromuscular disorders such as CMT2D, dHMN, and iSMA. In the cancer context, GARS1 may serve as a prognostic and immunological biomarker, especially in BLCA. Understanding GARS1 through genetic studies in patients provides insights into disease mechanisms and potential therapeutic targets for these neuromuscular and cancer diseases.