RARS2: Arginyl-tRNA Synthetase 2, Mitochondrial
A nuclear-encoded mitochondrial enzyme essential for protein synthesis and associated with pontocerebellar hypoplasia type 6 (PCH6).
Gene Information Card
| Symbol | RARS2 |
|---|---|
| Full Name | Arginyl-tRNA Synthetase 2, Mitochondrial |
| Gene Type | Protein coding |
| Chromosomal Location | 6q15 |
| NCBI Gene ID | 57017 ncbi.nlm.nih.gov/gene/57017 |
| Ensembl ID | ENSG00000113810 |
| UniProt ID | Q5T160 |
| OMIM ID | 611524 |
| HGNC ID | 21406 |
| Aliases | ArgRS, DALRD2, PRO1962, RP11-145E5.1 |
Description
RARS2 encodes the mitochondrial arginyl-tRNA synthetase, a nuclear-encoded enzyme that catalyzes the attachment of arginine to its cognate mitochondrial tRNA (tRNAArg). This aminoacylation reaction is essential for mitochondrial protein translation. Mutations in RARS2 cause pontocerebellar hypoplasia type 6 (PCH6), a severe autosomal recessive neurodegenerative disorder characterized by prenatal onset of cerebellar and brainstem atrophy, often with lactic acidosis and early lethality.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pontocerebellar hypoplasia type 6 (PCH6) | Loss-of-function mutations impair mitochondrial arginyl-tRNA charging, leading to defective mitochondrial protein synthesis, respiratory chain deficiency, and neurodegeneration. | ClinVar, OMIM #611523 |
| Combined oxidative phosphorylation deficiency (multiple case reports) | Reduced mitochondrial translation due to RARS2 deficiency results in multiple respiratory chain complex defects. | NCBI Gene, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Cerebellum | 12.5 | Medium |
| Cerebral cortex | 10.8 | Medium |
| Heart | 9.2 | Medium |
| Liver | 6.1 | Low |
| Skeletal muscle | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 14.3 | High expression |
| HeLa | 11.0 | Medium expression |
| SH-SY5Y | 9.8 | Medium expression |
| HepG2 | 6.5 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.25A>G (p.Lys9Glu) | Missense | Found in PCH6 families | Reduced enzyme activity and stability |
| c.470T>C (p.Leu157Pro) | Missense | Rare | Impaired mitochondrial localization |
| c.822_823del (p.Glu275fs) | Frameshift | Private mutation | Loss of function, truncated protein |
| c.1342C>T (p.Arg448Trp) | Missense | Reported in PCH6 | Decreased tRNA charging activity |
Mutation functional classification
Loss of Function (LOF)
Most reported RARS2 mutations are loss-of-function, leading to reduced or absent arginyl-tRNA synthetase activity in mitochondria.
Gain of Function (GOF)
No evidence of gain-of-function mutations in RARS2.
Dominant Negative (DN)
No dominant-negative mechanisms described; disease is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mitochondrial tRNA aminoacylation (Reactome R-HSA-379716)
• Respiratory electron transport (Reactome R-HSA-611105) – indirect via mitochondrial translation
Protein Summary
RARS2 is a 577-amino acid mitochondrial matrix protein that belongs to the class I aminoacyl-tRNA synthetase family. It contains a catalytic domain responsible for arginine activation and transfer to tRNAArg. The protein is synthesized in the cytosol and imported into mitochondria via an N-terminal mitochondrial targeting sequence. Defects in RARS2 disrupt mitochondrial protein synthesis, particularly affecting complexes I, III, IV, and V of the oxidative phosphorylation system, leading to energy deficiency and neurodegeneration.
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