GARS1: Glycyl-tRNA Synthetase 1
A key enzyme in protein translation and a causative gene in Charcot-Marie-Tooth disease and distal spinal muscular atrophy
Gene Information Card
| Symbol | GARS1 |
|---|---|
| Full Name | Glycyl-tRNA Synthetase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 7p14.3 |
| NCBI Gene ID | 2617 ncbi.nlm.nih.gov/gene/2617 |
| Ensembl ID | ENSG00000106105 |
| UniProt ID | P41250 |
| OMIM ID | 600287 |
| HGNC ID | 4162 |
| Aliases | GARS, GlyRS, SMAD1, CMT2D, DSMAV, HMN5, MGC87313 |
Description
GARS1 encodes glycyl-tRNA synthetase, a class II aminoacyl-tRNA synthetase that catalyzes the attachment of glycine to its cognate tRNA during protein translation. The enzyme functions as a homodimer and is essential for accurate protein synthesis. Mutations in GARS1 are associated with peripheral neuropathies, including Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). The gene is also implicated in cancer and autoimmune disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Charcot-Marie-Tooth disease type 2D (CMT2D) | Dominant-negative or loss-of-function mutations impair tRNA charging, leading to axonal degeneration in peripheral nerves. | ClinVar, OMIM |
| Distal spinal muscular atrophy type V (dSMA-V) | Mutations disrupt motor neuron survival via altered protein synthesis or gain-of-toxic function. | ClinVar, OMIM |
| Autoimmune myasthenia gravis | Autoantibodies against GARS1 may impair neuromuscular transmission. | UniProt, literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 14.2 | Medium |
| Spinal cord | 12.8 | Medium |
| Skeletal muscle | 18.5 | High |
| Heart | 15.1 | High |
| Liver | 10.3 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 16.0 | Neuronal model |
| HeLa (cervical carcinoma) | 12.5 | Epithelial |
| HepG2 (hepatocellular carcinoma) | 11.8 | Liver model |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Gly240Arg | Missense | Rare (CMT2D) | Dominant-negative; reduces tRNA charging activity |
| p.Ser581Leu | Missense | Rare (dSMA-V) | Gain-of-function; alters protein aggregation |
| p.Glu71Gly | Missense | Rare (CMT2D) | Loss-of-function; impairs dimerization |
Mutation functional classification
Loss of Function (LOF)
Reduced catalytic activity or dimer stability, leading to insufficient tRNA charging and protein synthesis defects.
Gain of Function (GOF)
Aberrant protein interactions or aggregation, causing toxic effects in motor neurons.
Dominant Negative (DN)
Mutant subunits disrupt wild-type dimer function, reducing overall enzymatic activity.
View complete mutation data：
Gene Ontology (GO)
| • glycine-tRNA ligase activity | • ATP binding |
| • tRNA binding | • protein homodimerization activity |
| • cytoplasm | • translation |
Pathways
• Aminoacyl-tRNA biosynthesis (KEGG: hsa00970)
• tRNA charging (Reactome: R-HSA-379716)
Protein Summary
Glycyl-tRNA synthetase (GlyRS) is a 685-amino-acid homodimeric enzyme that charges tRNA(Gly) with glycine. It contains an N-terminal WHEP domain involved in tRNA binding and a C-terminal catalytic domain. Beyond translation, GlyRS has roles in angiogenesis and immune signaling. Mutations cause peripheral neuropathy through both loss-of-function and gain-of-toxic-function mechanisms.
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