HARS1: Histidyl-tRNA Synthetase 1
A key enzyme in protein synthesis implicated in Charcot-Marie-Tooth disease and autoimmune disorders
Gene Information Card
| Symbol | HARS1 |
|---|---|
| Full Name | Histidyl-tRNA Synthetase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 5q31.3 |
| NCBI Gene ID | 3035 ncbi.nlm.nih.gov/gene/3035 |
| Ensembl ID | ENSG00000170445 |
| UniProt ID | P12081 |
| OMIM ID | 142810 |
| HGNC ID | 4816 |
| Aliases | HARS, HisRS, CMT2W |
Description
HARS1 encodes the cytoplasmic histidyl-tRNA synthetase, an enzyme that catalyzes the attachment of histidine to its cognate tRNA during protein synthesis. It belongs to the class II aminoacyl-tRNA synthetase family. Mutations in HARS1 are associated with Charcot-Marie-Tooth disease type 2W (CMT2W) and Usher syndrome type 3B. Autoantibodies against HARS1 are found in patients with idiopathic inflammatory myopathies, particularly anti-Jo-1 syndrome.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Charcot-Marie-Tooth disease type 2W | Loss-of-function mutations impair histidine charging, leading to peripheral neuropathy | ClinVar, OMIM |
| Usher syndrome type 3B | Biallelic missense mutations disrupt tRNA synthetase activity, causing sensorineural hearing loss and retinitis pigmentosa | OMIM, PubMed |
| Anti-Jo-1 syndrome | Autoantibodies target HARS1, contributing to myositis and interstitial lung disease | UniProt, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 15.2 | Medium |
| Brain | 12.8 | Medium |
| Heart | 10.5 | Medium |
| Skeletal Muscle | 9.3 | Low |
| Kidney | 14.1 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.5 | Ubiquitous expression |
| HEK293 | 16.2 | High expression |
| K562 | 12.0 | Moderate expression |
| HepG2 | 14.8 | High expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1210C>T (p.Arg404Trp) | Missense | Rare | Loss of function; associated with CMT2W |
| c.1129G>A (p.Gly377Arg) | Missense | Rare | Dominant negative; associated with CMT2W |
| c.946G>A (p.Glu316Lys) | Missense | Rare | Loss of function; associated with Usher syndrome |
Mutation functional classification
Loss of Function (LOF)
Missense mutations (e.g., p.Arg404Trp) reduce histidine charging activity, leading to peripheral neuropathy.
Gain of Function (GOF)
Not reported for HARS1.
Dominant Negative (DN)
p.Gly377Arg mutation exerts dominant negative effects, impairing dimerization and enzyme activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Aminoacyl-tRNA biosynthesis (KEGG: hsa00970)
• tRNA processing (Reactome: R-HSA-379716)
Protein Summary
HARS1 is a 509-amino acid protein that functions as a homodimer. Each subunit contains an N-terminal catalytic domain and a C-terminal anticodon-binding domain. The enzyme requires ATP and magnesium for histidine activation. Post-translational modifications include phosphorylation at Ser-51 and Ser-52, which may regulate activity. Autoantibodies against HARS1 are a hallmark of anti-Jo-1 syndrome.
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