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.

Keywords: HUPRA syndrome; SARS2; genetics; missense mutation; pulmonary hypertension.

FIGURE 1

Clinical findings of the patient with HUPRA syndrome.

FIGURE 2

(A) Family pedigree, mutation sites, and ACMG grade based on whole-exome sequencing. (B) Sanger sequencing validation of the patient. (C) Multiple sequence alignment of 227-Arg using T-coffee. (D) Region analysis of seryl-tRNA synthetase 2 using NCBI, two conserved domain is identified: COG4372 (54–162) and SerRS_Core (185–485). According to the dual-mode recognition of SerRS, 36 of the residues are located in the dimer-interface (marked in yellow highlight), and 227-Arg is one of these residues.

FIGURE 3

The structure analysis of SerRS variants using PyMOL 2.5.2, and the structure is optimized by molecule dynamics simulation to acquire the most stable configurations. The hydrogen bonds are marked with yellow dashes. (A) Configuration of SerRS wild type. (B) Configuration of SerRS p.Arg227Gln variant. (C) Configuration of SerRS p.Arg402His variant. (D) Configuration of SerRS p.Arg402His/p.Arg227Gln variants. All variants did not cause significant structure damage to SerRS. However, p.Arg227Gln and p.Arg402His/p.Arg227Gln variants lost the hydrogen bond of Arg-227 with Thr-335 and Glu-332, while acquired the hydrogen bond with His-346. p.Arg402His and p.Arg402His/p.Arg227Gln lost the hydrogen bond and ionic bonds between Arg-402 and Asp-390.