In a boy with a complex phenotype comprising Arts syndrome and PRPS1 superactivity (see 301835), Moran et al. (2012) identified a 424G-C transversion in exon 4 of the PRPS1 gene, resulting in a val142-to-leu (V142L) substitution at a highly conserved residue. Both the mother and grandmother were heterozygous for the mutation, which was not found in 202 control alleles. The patient had developmental delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing loss, and a Chiari I malformation. Laboratory studies showed increased serum uric acid and increased urinary hypoxanthine consistent with PRPS1 superactivity, but he did not have gout. In addition, he had recurrent infections and early death at age 27 months from infection, consistent with Arts syndrome. A maternal uncle with similar symptoms had died of pneumonia at age 2. Molecular modeling predicted that the substitution would disrupt allosteric sites involved in inhibition of PRPS1, resulting in a gain of enzyme function, and the ATP-binding site, resulting in a loss of enzyme function. Patient fibroblasts showed normal PRPP synthetase activity, whereas erythrocytes showed a loss of enzyme activity, suggesting that the effect of the V142L mutation on protein activity depends on cell type. Moran et al. (2012) postulated a gain-of-function effect in proliferating cells and a loss-of-function effect in postmitotic cells. The report indicated that PRPS1 missense mutations can cause a continuous spectrum of features ranging from progressive nonsyndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites affected.
