Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X-linked Sensorineural Deafness, DFN2

Department of Otolaryngology, University of Miami, FL 33136, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2009; 86(1):65-71. DOI: 10.1016/j.ajhg.2009.11.015
Source: PubMed


We report a large Chinese family with X-linked postlingual nonsyndromic hearing impairment in which the critical linkage interval spans a genetic distance of 5.41 cM and a physical distance of 15.1 Mb that overlaps the DFN2 locus. Mutation screening of the PRPS1 gene in this family and in the three previously reported DFN2 families identified four different missense mutations in PRPS1. These mutations result in a loss of phosphoribosyl pyrophosphate (PRPP) synthetase 1 activity, as was shown in silico by structural analysis and was shown in vitro by enzymatic activity assays in erythrocytes and fibroblasts from patients. By in situ hybridization, we demonstrate expression of Prps1 in murine vestibular and cochlea hair cells, with continuous expression in hair cells and postnatal expression in the spiral ganglion. Being the second identified gene associated with X-linked nonsyndromic deafness, PRPS1 will be a good candidate gene for genetic testing for X-linked nonsyndromic hearing loss.

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    • "His sister (subject II-1; Figure 1A) had developed prelingual sensorineural hearing loss in the first years of life, without any further signs of neurological dysfunction at current age of 42 years. This phenotype is fully compatible with the diagnosis of X-linked non-syndromic sensorineural hearing loss (DFN2) [5]. Her MRI showed discrete parietal and cerebellar atrophy as well (Figure 2C,D). "
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    ABSTRACT: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to loss-of-function mutations in PRPS1. As only few families have been described, knowledge about the relation between these syndromes, the phenotypic spectrum in patients and female carriers, and the relation to underlying PRS-I activity is limited. We investigated a family with a novel PRPS1 mutation (c.830A > C, p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests. The male index subject presented with an overlap of CMTX5 and Arts syndrome features, whereas his sister presented with prelingual DFN2. Both showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother. Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are phenotypic clusters on an intrafamilial continuum, including overlapping phenotypes even within individuals. The respective phenotypic presentation seems to be determined by the exact PRPS1 mutation and the residual enzyme activity, the latter being largely influenced by the degree of skewed X-inactivation. Finally, our findings show that brain atrophy might be more common in PRPS1-disorders than previously thought.
    Orphanet Journal of Rare Diseases 02/2014; 9(1):24. DOI:10.1186/1750-1172-9-24 · 3.36 Impact Factor
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    • "Mutations in the gene encoding phosphoribosyl pyrophosphate synthetase (PRS)-I, PRPS1 (MIM 311850), have been reported in four syndromes: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5, or Rosenberg-Chutorian syndrome; MIM 311070),1,2 PRS-I superactivity (MIM 300661),3 Arts syndrome (MIM 301835),4,5 and nonsyndromic sensorineural deafness (DFN2; MIM 304500).6 PRPS1 belongs to a family that comprises three highly conserved genes: PRPS1, PRPS2 (MIM 311860), and PRPS1L1 (MIM 611566).7,8 "
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    ABSTRACT: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is caused by mutations in the gene encoding phosphoribosyl pyrophosphate synthetase I (PRPS1). There has been only one case report of CMTX5 patients. The aim of this study was to identify the causative gene in a family with CMTX with peripheral neuropathy and deafness. A Korean family with X-linked recessive CMT was enrolled. The age at the onset of hearing loss of the male proband was 5 months, and that of steppage gait was 6 years; he underwent cochlear surgery at the age of 12 years. In contrast to what was reported for the first patients with CMTX5, this patient did not exhibit optic atrophy. Furthermore, there was no cognitive impairment, respiratory dysfunction, or visual disturbance. Assessment of his family history revealed two male relatives with very similar clinical manifestations. Electrophysiological evaluations disclosed sensorineural hearing loss and peripheral neuropathy. Whole-exome sequencing identified a novel p.Ala121Gly (c.362C>G) PRPS1 mutation as the underlying genetic cause of the clinical phenotype. A novel mutation of PRPS1 was identified in a CMTX5 family in which the proband had a phenotype of peripheral neuropathy with early-onset hearing loss, but no optic atrophy. The findings of this study will expand the clinical spectrum of X-linked recessive CMT and will be useful for the molecular diagnosis of clinically heterogeneous peripheral neuropathies.
    Journal of Clinical Neurology 10/2013; 9(4):283-288. DOI:10.3988/jcn.2013.9.4.283 · 1.70 Impact Factor
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    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).
    The American Journal of Human Genetics 04/2010; 86(4):506-18. DOI:10.1016/j.ajhg.2010.02.024 · 10.93 Impact Factor
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