MARS2 – Mitochondrial Disease

Biallelic pathogenic variants in MARS2 underlie a novel autosomal recessive mitochondrial disorder characterized by combined oxidative phosphorylation deficiency (COXPD25). A single patient was reported with compound heterozygous variants c.550C>T (p.Gln184Ter) and c.424C>T (p.Arg142Trp) in MARS2, confirmed by iPSC modeling from patient fibroblasts (PMID:39874649). No additional family segregation was described, representing Limited genetic evidence.

Functional studies in Drosophila Aats-met mutants and patient-derived cells demonstrate concordant loss‐of‐function effects on mitochondrial protein synthesis, Complex I activity, increased reactive oxygen species, and activation of the mitochondrial unfolded protein response (PMID:22448145). These data support a mechanism of recessive loss of function leading to oxidative phosphorylation failure. Additional cases are needed to strengthen the clinical validity. Key take-home: MARS2 variant screening enables molecular diagnosis of combined OXPHOS deficiency and guides genetic counseling.

References

• Stem cell research • 2025 • Generation of induced pluripotent stem cell line ISMMSi060-A from a patient with combined oxidative phosphorylation deficiency 25. PMID:39874649
• PLoS biology • 2012 • Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PMID:22448145

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