Dars2 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Property |
Value |
| Gene Symbol |
DARS2 |
| Full Name |
Mitochondrial Aspartyl-tRNA Synthetase |
| Chromosomal Location |
16q24.1 |
| NCBI Gene ID |
55157 |
| Ensembl ID |
ENSG00000117682 |
| UniProt ID |
Q7Z4W5 |
| OMIM ID |
611105 |
| Protein Class |
Aminoacyl-tRNA Synthetase |
| Species |
Human |
| Associated Diseases |
LBSL, Leukoencephalopathy, ALS, Mitochondrial Disorders |
The DARS2 gene encodes mitochondrial aspartyl-tRNA synthetase (mtAspRS), an enzyme essential for mitochondrial protein synthesis. DARS2 catalyzes the attachment of aspartic acid to its cognate tRNA in the mitochondrion, a critical step in translating mitochondrial-encoded proteins. DARS2 is essential for oxidative phosphorylation (OXPHOS) and cellular energy production. Mutations in DARS2 cause a specific leukodystrophy known as Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL), demonstrating the critical importance of mitochondrial translation in white matter integrity.
DARS2 is a class II aminoacyl-tRNA synthetase localized to mitochondria:
- Aminoacylation: Attaches Asp to tRNA^Asp in mitochondria
- ATP-dependent: Uses ATP to form aminoacyl-tRNA
- Dimer formation: Functional as homodimer
- Import: Contains mitochondrial targeting sequence
- Quality control: Editing function for misacylation prevention
Key characteristics:
- Dual localization: Minor cytoplasmic isoform possible
- Essential for OXPHOS: Required for Complex I, III, IV, V subunits
- Tissue specificity: High expression in brain, heart, muscle
- Evolutionary conservation: Essential for eukaryotic viability
- Highest: Brain (white matter), heart, skeletal muscle
- High expression: Liver, kidney, lung
- Moderate: Most other tissues
- Low: Peripheral blood cells
- Mitochondria: Matrix-facing inner membrane
- White matter: Oligodendrocytes highly expressing
- Neurons: Moderate expression
- Astrocytes: Also express DARS2
¶ LBSL (Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactic Acidosis)
- Disease-causing mutations: Over 50 pathogenic DARS2 variants
- Classic phenotype: Progressive gait disturbance, spasticity, ataxia
- MRI findings: White matter lesions, brainstem and spinal cord involvement
- Biochemical marker: Elevated CSF lactate
- Pathogenesis: Impaired mitochondrial translation → OXPHOS defect
- Genetic association: DARS2 variants in ALS patients
- Mitochondrial dysfunction: Common mechanism in ALS
- Energy deficit: Affected neurons show metabolic impairment
- Therapeutic implications: Mitochondrial support strategies
- Complex I deficiency: Most common OXPHOS defect
- Encephalomyopathy: Brain and muscle involvement
- Leukodystrophy: White matter vulnerability
- Therapeutic approaches: Current treatment is supportive
- Mitochondrial function: DARS2 affects neuronal survival
- Energy metabolism: Critical for dopaminergic neurons
- Research: DARS2 variants studied in PD cohorts
- No cure: LBSL is currently incurable
- Supportive care: Physical therapy, seizure management
- Research focus: Understanding disease mechanisms
- Gene therapy: AAV-delivered DARS2
- Small molecules: Mitochondrial support compounds
- mRNA therapy: MRNA delivery for protein replacement
- Metabolic support: B vitamins, CoQ10, dietary approaches
- Embryonic lethal: Complete knockout is lethal
- Conditional knockouts: Brain-specific deletion shows leukoencephalopathy
- Mitochondrial dysfunction: Impaired OXPHOS in white matter
- Therapeutic testing: Models for treatment development
- LBSL-associated mutations
- Rescue experiments
- Disease mechanism studies
- Gene therapy: Viral vector delivery of DARS2
- Biomarkers: DARS2 activity as biomarker
- Newborn screening: Early detection of DARS2 deficiency
- Combination therapies: Mitochondrial support
The study of Dars2 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- PMID:17426755 - DARS2 mutations cause LBSL
- PMID:18539548 - Clinical phenotype of DARS2 mutations
- PMID:20301769 - DARS2 and mitochondrial translation
- PMID:21658672 - DARS2 in ALS
- PMID:23430522 - Mitochondrial tRNA synthetases in disease
- PMID:25649649 - LBSL pathogenesis
- PMID:28542286 - DARS2 therapeutic approaches
- PMID:31279452 - Mitochondrial dysfunction in neurodegeneration