Novel variants of seryl-tRNA synthetase resulting in HUPRA syndrome featured in pulmonary hypertension

Abstract

Hyperuricemia, pulmonary hypertension, and renal failure in infancy and alkalosis syndrome (HUPRA syndrome) is an ultrarare mitochondrial disease that is characterized by hyperuricemia, pulmonary hypertension, renal failure, and alkalosis. Seryl-tRNA synthetase 2 (SARS2) gene variants are believed to cause HUPRA syndrome, and these variants result in the loss of function of seryl-tRNA synthetase. Eventually, mutated seryl-tRNA synthetase is unable to catalyze tRNA synthesis and leads to the inhibition of the biosynthesis of mitochondrial proteins. This causes oxidative phosphorylation (OXPHOS) system impairments. To date, five mutation sites in the SARS2 gene have been identified. We used whole-exome sequencing and Sanger sequencing to find and validate a novel compound heterozygous variants of SARS2 [c.1205G>A (p.Arg402His) and c.680G>A (p.Arg227Gln)], and in silico analysis to analyze the structural change of the variants. We found that both variants were not sufficient to cause obvious structural damage but changed the intermolecular bond of the protein, which could be the cause of HUPRA syndrome in this case. We also performed the literature review and found this patient had significant pulmonary hypertension and minor renal dysfunction compared with other reported cases. This study inspired us to recognize HUPRA syndrome and broaden our knowledge of gene variation in PH.

Protein–Protein Interactions of Seryl-tRNA Synthetases with Emphasis on Human Counterparts and Their Connection to Health and Disease

“…Pathogenic variants in the SARS1 gene encoding cytosolic SerRS have been implicated in neurodevelopmental, neurological, and movement disorders with various symptoms [69][70][71][72][73]. Several mutations in the SARS2 gene encoding mitochondrial SerRS have been associated with conditions such as HUPRA (hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis) syndrome and progressive spastic paresis [74][75][76][77][78][79]. Transcriptomic and proteomic data revealed aberrant cytosolic and mitochondrial SerRS mRNA and protein levels, depending on the cancer type [17].…”

“…Most of these variants showed reduced serylation activity, which could explain the observed symptoms [71][72][73][74]76,78]. However, for some of the variants, the effect is unknown, which creates the possibility that impaired SerRS PPIs may be the cause of the symptoms that should be taken into account when investigating these disorders [70,75,77,79].…”