title: The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.
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.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Robusto
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.affiliation: Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Previtali
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Caccia
authors.affiliation: Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Benzoni
authors.affiliation: Haemostasis Research Center, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy.
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cesarani
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Wangsheng
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Primignani
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D054062:Deaf-Blind Disorders / Q000235:genetics*; D003638:Deafness / Q000235:genetics; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics*
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase