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MARS2 – Spastic Ataxia 3

Biallelic complex rearrangements in MARS2 were identified in autosomal recessive spastic ataxia with leukoencephalopathy (spastic ataxia 3) patients, defining a novel genetic subtype (PMID:22448145). Two loss-of-function alleles were reported, including c.682_949del (p.Gly228fs) ([PMID:22448145]). The inheritance is autosomal recessive.

Functional modeling in Drosophila Aats-met mutants recapitulated age-dependent photoreceptor degeneration, impaired oxidative phosphorylation, increased reactive oxygen species, and activation of the mitochondrial unfolded protein response. Patient fibroblasts exhibited decreased MARS2 protein, reduced mitochondrial translation, diminished Complex I activity, and elevated reactive oxygen species, consistent with a loss-of-function mechanism ([PMID:22448145]).

Key take-home: MARS2 loss-of-function variants underlie spastic ataxia 3, enabling molecular diagnosis, carrier screening, and future targeted therapies.

References

  • 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)

Gene–Disease Association

Limited

Single multi-patient study showing biallelic MARS2 rearrangements in ARSAL patients with consistent clinical phenotype ([PMID:22448145])

Genetic Evidence

Limited

Identification of two loss-of-function alleles (c.682_949del (p.Gly228fs)) in ARSAL probands ([PMID:22448145])

Functional Evidence

Moderate

Drosophila Aats-met loss-of-function models recapitulate neurodegeneration and mitochondrial dysfunction; patient cells show reduced MARS2 protein, impaired mitochondrial translation, and Complex I deficiency ([PMID:22448145])