Arts syndrome is caused by loss-of-function mutations in PRPS1

Abstract

Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.

Figure 1.

Pedigree of family F (A) and the overlapping linkage intervals between family F (B) and family N032 (C). Indicated are the positions of the genes analyzed in patients as described in this article (bold font) and as previously described by de Brouwer et al.

Figure 2.

Chromatograms showing the nucleotide changes in PRPS1. A, c.398A→C transversion in exon 3 in individual III-2 of family F. B, Segregation of the mutant allele within family F (see also fig. 1A), as shown by ApoI restriction analysis. C, c.455T→C transition in exon 4 in individual IV-2 of family N032. D, Segregation of the mutant allele within family N032 (family members are numbered as in the work of Arts et al.14), as shown by BsmFI restriction analysis.

Figure 3.

Three-dimensional model of PRS-I as a hexamer (A and B) and close-ups of the two regions of PRS-I that contain the mutations p.Q133P (C and E) and p.L152P (D and F). The red spheres indicate the positions of the mutated amino acid residues in the PRS-I hexamer. The yellow dotted lines represent the hydrogen bonds.