DARS2 – Mitochondrial Disease

DARS2 encodes the mitochondrial aspartyl-tRNA synthetase (mtAspRS), a critical enzyme for mitochondrial protein synthesis. Autosomal recessive bi-allelic variants in DARS2 cause mitochondrial dysfunction manifesting as leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), a well-defined mitochondrial disease phenotype within the broader spectrum of primary mitochondrial disorders.

A cross-sectional study of 78 patients from two international cohorts identified compound heterozygous DARS2 mutations in all individuals, with 94% harboring a splice-site defect in intron 2 (PMID:24566671). Sixty distinct pathogenic alleles were reported across 66 unrelated probands, demonstrating marked allelic heterogeneity and supporting a strong gene–disease relationship.

Clinical presentations range from rapidly progressive infantile disease to mild adult-onset forms; hallmark features include progressive ataxia, spasticity, characteristic MRI abnormalities of the brainstem and spinal cord, and elevated lactate on MR spectroscopy.

The variant spectrum includes splice-site (e.g., c.492+2T>C), missense, nonsense and frameshift changes. The recurrent intron 2 splice mutation c.492+2T>C is observed in most patients (PMID:38125072), while additional alleles such as c.455G>T (p.Cys152Phe) and c.1173_1179del (p.Ala392fs) further diversify the mutational landscape.

Functional assays of patient-derived cells reveal reduced mtAspRS expression, defective dimerization and decreased enzymatic activity (PMID:23216004). Yeast complementation models demonstrate loss of oxidative growth rescue by pathogenic mtAspRS variants (PMID:35820270). Splice-modulating compounds such as cantharidin correct intron 2 mis-splicing in vitro, highlighting potential therapeutic avenues.

Collectively, strong genetic and experimental concordance establish DARS2 as a definitive cause of mitochondrial disease. Molecular diagnosis of DARS2 variants has high clinical utility for diagnostic confirmation, family counseling, and guiding targeted therapeutic development. Key take-home: DARS2 screening should be integrated into mitochondrial disease diagnostic panels for prompt and accurate diagnosis.

References

• Brain : a journal of neurology | 2014 | Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. PMID:24566671
• The Biochemical journal | 2013 | Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways. PMID:23216004
• Molecular genetics and metabolism | 2022 | Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. PMID:35820270
• Molecular genetics and metabolism reports | 2024 | Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL): Report of a new family and a novel DARS2 mutation. PMID:38125072

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