PRPS1 mutations: four distinct syndromes and potential treatment

Abstract

Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).

Figure 1

Three-Dimensional Model of PRS-I as a Hexamer and a Close-Up of the Regions that Contain the Amino Acid Substitutions (A) Three-dimensional model of PRS-I as a hexamer, with the six monomers labeled with different colors. (B–G) Seven substitutions that result in PRS-I superactivity: p.D52H (B), p.N114S (C), p.L129I (D), p.D183H (E), p.A190V (F), and p.H193L (G). Note that pH193Q has a similar effect on the PRS-I structure as p.H193L. (H–K) Four substitutions that cause Arts syndrome and CMTX5: p.Q133P (H), p.L152P (I), p.E43D (J), and p.M115T (K). (L–O) Four substitutions that result in DFN2: p.D65N (L), p.A87T (M), p.I290T (N), and p.G306R (O). All substitutions are shown for monomer 1. Homodimer interactions are shown between monomer 1 (blue) and monomer 2 (cyan). Trimer interactions are shown between monomer 1, monomer 2, and monomer 6 (purple). Hydrogen bonds are indicated with yellow dashed lines. Strong interatomic steric hindrance is indicated with orange dashed arrows. The effect of PRPS1 mutations on the structure of PRS-I was examined with the crystal structures of the human protein from Li et al. The altered amino acid side chains in the model were positioned with a backbone-dependent rotamer library, as implemented in the YASARA program.

Figure 2

Simplified Overview of the Purine Metabolism Pathway The scheme is derived from KEGG Pathways hsa00230 (purine metabolism) and hsa00240 (pyrimidine metabolism). Indicated in red is the alternative pathway to replenish purine nucleotides via SAM. Enzymes central in this review are highlighted by blue boxes. PRS-I is printed in bold. Boxes show the essential role of PRPP in the purine metabolism. Dashed arrows indicate multiple intermediate steps that are not shown. PRPP is also used for the de novo synthesis of pyrimidines, as indicated by the arrow to UMP, the central intermediate in pyrimidine pathway. In addition, PRPP is essential for pyridine nucleotide (NAD/NADP) synthesis (not shown).