SARS2 – HUPRA Syndrome

HUPRA syndrome (MONDO:0013458) is a rare autosomal recessive mitochondrial disorder characterized by hyperuricemia, pulmonary arterial hypertension, renal failure in infancy, and metabolic alkalosis. It was first delineated in consanguineous Palestinian kindreds and has since been linked to pathogenic variants in SARS2.

In 2011 (PMID:21255763), genome-wide homozygosity mapping identified a homozygous NM_017827.4:c.1169A>G (p.Asp390Gly) variant in SARS2 in two affected siblings and a third unrelated infant. All three probands presented in early infancy with severe renal tubulopathy (hyperuricemia and metabolic alkalosis), progressive pulmonary hypertension, and rapid renal failure. The Asp390 residue resides in the enzyme’s active site, and the variant segregated fully with disease in the consanguineous pedigree.

In 2013 (PMID:24034276), a second homozygous NM_017827.4:c.1205G>A (p.Arg402His) variant was reported in a separate sibling pair presenting with the classical HUPRA phenotype. This ultra-rare variant lies adjacent to Asp390 in the C-terminal globular domain and segregated with disease in both siblings. Combining both studies yields five probands across four unrelated families with homozygous SARS2 variants consistent with autosomal recessive inheritance; the carrier frequency for p.Asp390Gly in the Palestinian isolate was 1:15.

Clinically, affected individuals uniformly exhibit hyperuricemia (HP:0002149), pulmonary arterial hypertension (HP:0002092), progressive renal failure, and metabolic alkalosis (HP:0001948). The neonatal onset of severe tubulopathy with concomitant pulmonary vascular pathology is pathognomonic and guides targeted genetic testing.

Functional assays in patient-derived lymphoblasts demonstrated a marked reduction in aminoacylation of mitochondrial tRNASer(AGY) due to p.Asp390Gly, with selective degradation of uncharged tRNASer transcripts and impaired oxidative phosphorylation (PMID:21255763). Rescue of mitochondrial translation and respiratory function was achieved by overexpression of wild-type SARS2 in induced pluripotent stem cells.

In vivo mouse models of SARS2 deficiency revealed embryonic lethality in homozygotes and reduced muscle-specific tRNASer levels with mild myopathy in heterozygotes, confirming haploinsufficiency as the pathogenic mechanism (PMID:36350636). These data corroborate the critical role of SARS2 in mitochondrial protein synthesis and support a loss-of-function disease model.

The combined genetic, biochemical, and animal-model evidence establishes a strong clinical validity for SARS2 in HUPRA syndrome. Inclusion of SARS2 in diagnostic panels for early-onset tubulopathies and pulmonary hypertension facilitates timely diagnosis and genetic counseling.

References

• BMC Nephrology • 2013 • A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome. PMID:24034276
• American Journal of Human Genetics • 2011 • Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. PMID:21255763
• Nucleic Acids Research • 2022 • Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease. PMID:36350636

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