Multiple mechanisms lead to loss-of-function effects of pathogenic SARS2 variants.

Seryl-tRNA synthetase 2 (SARS2) encodes the enzyme responsible for charging tRNA with serine in the mitochondria. SARS2 has been associated with a spectrum of recessive diseases including HUPRA syndrome and progressive spastic paresis. Previous studies showed that pathogenic SARS2 variants cause decreased tRNA charging; however, the mechanism by which specific variants lead to distinct recessive phenotypes has not been defined. To address this lack of knowledge, we studied an allelic series of 11 pathogenic SARS2 variants for differential effects on mitochondrial function. These efforts revealed compelling variant-dependent effects on oxygen consumption that will be useful for genotype-phenotype correlations. Interestingly, certain variants (including the most commonly detected pathogenic SARS2 variant, R402H) did not affect mitochondrial function in our model system. Computational and functional studies revealed that two missense variants in exon 13 (D390G and R402H) reduce exon inclusion, suggesting loss-of-function effects via impaired transcript processing. Overall, this study expands our understanding of SARS2 biology, reveals differential effects that pathogenic variants have on SARS2 function, and provides the foundation for defining the clinical heterogeneity of patient phenotypes.