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

Michela Robusto, Mingyan Fang, Rosanna Asselta, Pierangela Castorina, Stefano C. Previtali, Sonia Caccia, Elena Benzoni, Raimondo De Cristofaro, Cong Yu, Antonio Cesarani, Xuanzhu Liu, Wangsheng Li, Paola Primignani, Umberto Ambrosetti, Xun Xu, Stefano Duga, Giulia Soldà

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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.

Original languageEnglish
Pages (from-to)766-773
Number of pages8
JournalEuropean Journal of Human Genetics
Volume23
Issue number6
DOIs
Publication statusPublished - Jun 15 2015

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ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Robusto, M., Fang, M., Asselta, R., Castorina, P., Previtali, S. C., Caccia, S., Benzoni, E., De Cristofaro, R., Yu, C., Cesarani, A., Liu, X., Li, W., Primignani, P., Ambrosetti, U., Xu, X., Duga, S., & Soldà, G. (2015). The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. European Journal of Human Genetics, 23(6), 766-773. https://doi.org/10.1038/ejhg.2014.168