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.
The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy / M. Robusto, M. Fang, R. Asselta, P. Castorina, S.C. Previtali, S. Caccia, E. Benzoni, R. De Cristofaro, C. Yu, A. Cesarani, X. Liu, W. Li, P. Primignani, U. Ambrosetti, X. Xu, S. Duga, G. Soldà. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - 23:6(2015 Jun), pp. 766-773.
|Titolo:||The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy|
|Parole Chiave:||of-function mutations; phosphoribosylpyrophosphate synthetase; PRPS1 mutation; arts syndrome; force-field; protein; deafness; reveals; encodes; family|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/13 - Biologia Applicata
Settore MED/32 - Audiologia
|Data di pubblicazione:||giu-2015|
|Data ahead of print / Data di stampa:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/ejhg.2014.168|
|Appare nelle tipologie:||01 - Articolo su periodico|