title: A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.
abstract: Gap junctions are intercellular channels that mediate rapid intercellular communication. They consist of connexins, small transmembrane proteins that belong to a large family found throughout the animal kingdom. In the skin, several connexins are expressed and are involved in the regulation of epidermal growth and differentiation. One of the skin expressed gap junction genes is GJB2, which codes for connexin 26 and is associated with a wide variety of keratinisation disorders. Here, we report on a family with a novel GJB2 mutation (p.His73Arg) causing a syndrome of focal palmoplantar keratoderma with severe progressive sensorineural hearing impairment, a phenotype reminiscent of Vohwinkel syndrome. Using fluorescent connexin fusion proteins, we show that the mutation induces a transport defect similar to that found for the Vohwinkel syndrome mutation p.Asp66His. Co-transfection into cells expressing wild type connexin26 shows that the mutant has a dominant negative effect on connexin trafficking. We suggest that there may be a weak genotype-phenotype correlation for mutations in GJB2.
authors.forename: E A
authors.initials: EA
authors.lastname: de Zwart-Storm
authors.forename: H
authors.initials: H
authors.lastname: Hamm
authors.forename: J
authors.initials: J
authors.lastname: Stoevesandt
authors.forename: P M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: P E
authors.initials: PE
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: van Geel
authors.forename: M A M
authors.initials: MA
authors.lastname: van Steensel
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism*; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D005838:Genotype; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014162:Transfection
chemical_list: D017630:Connexins; D017931:DNA Primers; D018076:DNA, Complementary; C000607042:GJB2 protein, human; D011993:Recombinant Fusion Proteins; D000072259:Connexin 26