title: Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment.
abstract: Mutations in GJB2, which encodes the gap junction protein connexin 26 (Cx26), are one of the major causes for inherited and sporadic nonsyndromic hearing impairment. This study aimed to functionally characterize more frequent GJB2 mutations identified in patients showing nonsyndromic hearing impairment. Following injection of wild type and mutated cRNA in Xenopus oocytes, Cx26 hemichannel activity was measured by depolarization activated conductance in noncoupled oocytes. All mutants showed a partially or completely defective phenotype, except (V27I)Cx26, a polymorphism tested as positive control. Coexpression of wild type and mutant Cx26 injected at equimolar levels revealed that p.M34T, p.V37I and p.I82M, but not p.G59V, p.L90P, p.R127H and p.R143W exert a dominant inhibitory effect. When coexpressed with Cx30, a connexin partially colocalized with Cx26 in the cochlea, all mutants had a dominant behavior. This study provides data that might be important for the improvement of genetic diagnosis and counseling for patients with hearing impairment.
authors.affiliation: Institute of Physiology I, University of Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Palmada
authors.forename: K
authors.initials: K
authors.lastname: Schmalisch
authors.forename: C
authors.initials: C
authors.lastname: Böhmer
authors.forename: N
authors.initials: N
authors.lastname: Schug
authors.forename: M
authors.initials: M
authors.lastname: Pfister
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.forename: N
authors.initials: N
authors.lastname: Blin
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D003051:Cochlea / Q000378:metabolism / Q000503:physiopathology; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics; D005260:Female; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D000075302:Connexin 30; D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26; D011188:Potassium