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Eur J Hum Genet. 2015 Jun;23(6):766-73. doi: 10.1038/ejhg.2014.168. Epub 2014 Sep 3.

The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.

Author information

1
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
2
BGI-Shenzhen, Shenzhen, China.
3
Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy.
4
Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
5
Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
6
Haemostasis Research Center, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy.

Abstract

Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype-phenotype correlation.

PMID:
25182139
PMCID:
PMC4270732
DOI:
10.1038/ejhg.2014.168
[Indexed for MEDLINE]
Free PMC Article

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