PRPS1 – Phosphoribosylpyrophosphate Synthetase Superactivity

Phosphoribosylpyrophosphate synthetase 1 (PRS-I), encoded by PRPS1, is a key enzyme in de novo and salvage purine biosynthesis. Gain-of-function mutations in PRPS1 cause phosphoribosylpyrophosphate synthetase superactivity, characterized by congenital hyperuricemia, hyperuricosuria, gout, urolithiasis, plus neurological and immunological features.

Three distinct missense variants in PRPS1 (c.424G>C (p.Val142Leu), c.573G>C (p.Leu191Phe), c.520G>C (p.Gly174Arg)) have been identified in four affected individuals from three unrelated families. The c.424G>C (p.Val142Leu) variant was found in a male proband with uric acid overproduction, developmental delay, hypotonia, hearing loss, and recurrent infections (PMID:22246954). The c.573G>C (p.Leu191Phe) variant segregated in a family with a 7-year-old boy and his hyperuricemic mother (PMID:28742244). A 16-year-old female with nephrolithiasis harbored c.520G>C (p.Gly174Arg) (PMID:30423175). One additional affected relative demonstrates segregation in the second family (PMID:28742244).

Inheritance is X-linked. Hemizygous males typically display full enzyme superactivity, whereas heterozygous females exhibit variable mild hyperuricemia and gout symptoms due to X-inactivation. Segregation was documented in one pedigree (affected mother and son) (PMID:28742244).

Functional assays consistently demonstrate PRPS1 gain-of-function. Enzyme activity measurements confirm elevated PRPP synthetase activity in erythrocytes and fibroblasts: markedly increased activity with c.573G>C (p.Leu191Phe) (PMID:28742244) and reduced ADP-mediated inhibition with c.520G>C (p.Gly174Arg) (PMID:30423175). Molecular modeling predicts disruption of allosteric regulatory sites and ATP-binding by p.Val142Leu (PMID:22246954).

The cumulative evidence supports a mechanism of altered allosteric regulation leading to tissue-specific PRPP synthetase superactivity. No animal models for this gain-of-function phenotype have been reported, but concordant biochemical and structural data across multiple variants reinforce pathogenicity.

Additional variant discovery and long-term natural history data are limited. Key take-home: PRPS1 gain-of-function mutations cause an X-linked spectrum of PRPP synthetase superactivity, and molecular testing should be considered in patients with unexplained congenital hyperuricemia, especially when accompanied by neurological or immunological features.

References

• American journal of medical genetics. Part A • 2012 • Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. PMID:22246954
• American journal of medical genetics. Part A • 2017 • Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies. PMID:28742244
• Rheumatology (Oxford, England) • 2018 • Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females. PMID:30423175

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