DARS2: Aspartyl-tRNA Synthetase 2, Mitochondrial
A nuclear-encoded mitochondrial enzyme essential for protein synthesis and implicated in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL).
Gene Information Card
| Symbol | DARS2 |
|---|---|
| Full Name | Aspartyl-tRNA Synthetase 2 (mitochondrial) |
| Gene Type | Protein coding |
| Chromosomal Location | 1q25.1 |
| NCBI Gene ID | 55157 ncbi.nlm.nih.gov/gene/55157 |
| Ensembl ID | ENSG00000117593 |
| UniProt ID | Q6PI48 |
| OMIM ID | 611105 |
| HGNC ID | 25544 |
| Aliases | ASP-RS, mtAspRS, DARS2_HUMAN |
Description
DARS2 encodes the mitochondrial aspartyl-tRNA synthetase, a nuclear-encoded enzyme that catalyzes the attachment of aspartate to its cognate mitochondrial tRNA (tRNA-Asp). This aminoacylation reaction is essential for mitochondrial protein translation. Biallelic pathogenic variants in DARS2 cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a rare autosomal recessive neurodegenerative disorder.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) | Impaired mitochondrial aspartyl-tRNA charging leads to defective mitochondrial protein synthesis, causing energy deficiency in CNS white matter tracts. | ClinVar, OMIM |
| Mitochondrial respiratory chain deficiency (secondary) | Reduced mitochondrial translation due to DARS2 deficiency impairs assembly of OXPHOS complexes. | NCBI Gene, UniProt |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Heart | 10.2 | Medium |
| Skeletal Muscle | 8.9 | Medium |
| Liver | 6.1 | Low |
| Kidney | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.3 | Moderate expression |
| HeLa | 11.8 | Moderate expression |
| SH-SY5Y | 9.5 | Moderate expression |
| HepG2 | 7.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.228-21_228-18delTTAA | Intronic deletion | Common (founder) | Splicing defect, reduced functional protein |
| c.492+2T>C | Splice donor | Rare | Exon skipping, loss of function |
| p.Arg263His | Missense | Rare | Impaired catalytic activity |
| p.Leu376Val | Missense | Rare | Reduced tRNA binding affinity |
Mutation functional classification
Loss of Function (LOF)
Most DARS2 mutations are loss-of-function, leading to reduced mitochondrial aspartyl-tRNA synthetase activity and impaired mitochondrial translation.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
No dominant-negative mutations reported; disease is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mitochondrial tRNA aminoacylation (Reactome R-HSA-379716)
• Mitochondrial translation (Reactome R-HSA-5368287)
• Respiratory electron transport (Reactome R-HSA-611105)
Protein Summary
DARS2 encodes a 645-amino acid mitochondrial aspartyl-tRNA synthetase (mtAspRS) belonging to the class II aminoacyl-tRNA synthetase family. The protein is imported into the mitochondrial matrix where it functions as a homodimer to catalyze the ATP-dependent ligation of aspartate to the 3' end of mitochondrial tRNA-Asp. This enzyme is critical for mitochondrial protein synthesis; its deficiency leads to impaired oxidative phosphorylation and the neurodegenerative phenotype observed in LBSL.
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