MARS2 – Combined Oxidative Phosphorylation Deficiency 25

MARS2 encodes the mitochondrial methionyl-tRNA synthetase, and biallelic pathogenic variants have been linked to Combined Oxidative Phosphorylation Deficiency 25 (COXPD25) in an autosomal recessive manner. In one reported patient, compound heterozygous variants c.550C>T (p.Gln184Ter) and c.424C>T (p.Arg142Trp) were identified in MARS2 (1 proband) (PMID:39874649). No additional familial segregation data are available. Patient‐derived iPSC line ISMMSi060-A maintained normal morphology, pluripotency marker expression, genome integrity, and differentiation potential, confirming viability despite MARS2 disruption (PMID:39874649). In Drosophila, Aats-met (MARS2 homolog) mutants exhibit age-dependent photoreceptor degeneration, reduced lifespan, oxidative phosphorylation defects, elevated reactive oxygen species, and mitochondrial unfolded protein response activation. Patient cells with complex MARS2 rearrangements also show decreased MARS2 protein levels, impaired mitochondrial protein synthesis, reduced Complex I activity, and increased ROS (PMID:22448145). Collectively, these data support a loss-of-function mechanism; however, the evidence for COXPD25 remains limited to a single proband. Key Take-home: Biallelic MARS2 variants underlie COXPD25, warranting inclusion in diagnostic gene panels for mitochondrial disorders.

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

Evidence Based Scoring (AI generated)