title: A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss.
abstract: Hereditary hearing loss (HHL) is a common disorder accounting for at least 60% of prelingual deafness. It is characterized by a large genetic heterogeneity, and despite the presence of a major gene, still there is a need to search for new causative mutations/genes. Very recently, a mutation within ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) gene (P2RX2) at DNFA41 locus has been reported leading to a bilateral and symmetrical sensorineural non-syndromic autosomal dominant HHL in two Chinese families. We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus. Molecular analyses of P2RX2 identified a novel missense mutation (p.Gly353Arg) affecting a residue highly conserved across species. Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the 'neck' of the region responsible for ion channel gating should have a high energetic cost and should lead to a severely destabilization of the fold. The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL.
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Via dell'Istria, 34137 Trieste, Italy. Electronic address: flavio.faletra@burlo.trieste.it.
authors.forename: Flavio
authors.initials: F
authors.lastname: Faletra
authors.affiliation: University of Trieste, Trieste, Italy. Electronic address: giorgia.girotto@burlo.trieste.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Girotto
authors.affiliation: University of Trieste, Trieste, Italy. Electronic address: pio.dadamo@burlo.trieste.it.
authors.forename: Adamo Pio
authors.initials: AP
authors.lastname: D'Adamo
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Via dell'Istria, 34137 Trieste, Italy. Electronic address: diego.vozzi@burlo.trieste.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Vozzi
authors.affiliation: University of Trieste, Trieste, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Via dell'Istria, 34137 Trieste, Italy; University of Trieste, Trieste, Italy. Electronic address: paolo.gasparini@burlo.trieste.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
mesh_terms: D000595:Amino Acid Sequence; D003638:Deafness / Q000235:genetics; D005260:Female; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D058476:Receptors, Purinergic P2X2 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C546401:P2RX2 protein, human; D058476:Receptors, Purinergic P2X2
keywords: ADNSHL; DFNA41; HHL; HL; Mutation; NSHL; P2RX2; autosomal dominant non-syndromic hearing loss; hearing loss; hereditary hearing loss; non-syndromic hearing loss; p.Gly353Arg