The relationship between MARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2022. The MARS2 gene encodes mitochondrial methionyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits.
The MARS2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22448145). This paper described the molecular etiologies in families originally reported in 2006 (PMID: 16672289). While various names have been given to the constellation of features seen in those with MARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MARS2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (three complex rearrangements, each determined to be a founder variant within the French-Canadian population, one missense variant, and one stop-gained variant) identified in five individuals from two publications (PMIDs: 22448145, 25754315). Affected individuals were reported to have leukoencephalopathy, cerebellar vermis atrophy, dystonia, ataxia, spasticity, and dysarthria. The phenotype of affected individuals with the French-Canadian founder variant or other complex rearrangements has been termed autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL; PMID: 22448145). The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in HEK293 cells showing disrupted mitochondrial protein translation, evidence of mitochondrial dysfunction in patient cells, and early lethality and mitochondrial dysfunction in two independent Drosophila models, each homozygous for a missense change (PMID: 22448145).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 4, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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