title: Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes.
abstract: Mutations in the GJB2 gene-encoding connexin 26 (Cx26) have been linked to skin disorders and genetic deafness. However, the severity and type of the skin disorders caused by Cx26 mutations are heterogeneous. Here we explored the effect of Cx26 KID syndrome-associated mutations, G12R, S17F, and D50N on channel function. The Cx26 N14K mutation was also examined that is associated with deafness but has a skin disorder distinct from the KID syndrome mutations. The proteins were all expressed in Xenopus oocytes with levels equal to wild-type Cx26. The G12R, N14K, and D50N mutations resulted in larger hemichannel currents than the wild-type-expressing cells, but the S17F mutation resulted in a complete loss of hemichannel activity. Elevated hemichannel activity correlated with an increased cell death. This result could be reversed through the elevation of calcium (Ca2+) in the extracellular media. Functional gap junctions were only produced by paired N14K cells, which had a similar conductance level to wild type, even though they exhibited a complete loss of voltage sensitivity. This set of data confirms that aberrant hemichannel activity is a common feature of Cx26 mutations associated with KID syndrome, and this may contribute to a loss of cell viability and tissue integrity.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794-8661, USA.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Lee
authors.forename: Adam M
authors.initials: AM
authors.lastname: Derosa
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000502:physiology; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D003638:Deafness / Q000209:etiology / Q000235:genetics*; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D007057:Ichthyosis / Q000209:etiology / Q000235:genetics*; D007634:Keratitis / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D014981:Xenopus
chemical_list: D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; D000072259:Connexin 26; D002118:Calcium