Biallelic loss-of-function and reduced-function variants in RARS2– which encodes a mitochondrial arginine-tRNA synthetase – result in disease through impaired protein translation and subsequent mitochondrial dysfunction. Reported pathogenic variants include missense substitutions, splice-site alterations, truncations/frameshifts predicted to undergo nonsense-mediated decay, and at least one functionally validated promoter variant that resulted in reduced gene expression. Notably, reports of individuals with two unequivocal null alleles are lacking, raising the possibility that complete loss of RARS2 function is incompatible with life. This observation suggests that residual RARS2 activity may be sufficient to modulate disease severity and could contribute to the clinical variability observed among affected individuals.
RARS2