title: Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.
abstract: Mutations in the human GJB2 gene, which encodes connexin26 (Cx26), underlie various forms of hereditary deafness and skin disease. While it has proven difficult to discern the exact pathological mechanisms that cause these disorders, studies have shown that the loss or abnormal function of Cx26 protein has a profound effect on tissue homeostasis. Here, we used the Xenopus oocyte expression system to examine the functional characteristics of a Cx26 mutation (G45E) that results in keratitis-ichthyosis-deafness syndrome (KIDS) with a fatal outcome. Our data showed that oocytes were able to express both wild-type Cx26 and its G45E variant, each of which formed hemichannels and gap junction channels. However, Cx26-G45E hemichannels displayed significantly greater whole cell currents than wild-type Cx26, leading to cell lysis and death. This severe phenotype could be rescued in the presence of elevated Ca(2+) levels in the extracellular milieu. Cx26-G45E could also form intercellular channels with a similar efficiency as wild-type Cx26, however, with increased voltage sensitive gating. We also compared Cx26-G45E with a previously described Cx26 mutant, A40V, which has an overlapping human phenotype. We found that both dominant Cx26 mutants elicited similar functional consequences and that cells coexpressing mutant and wild-type connexins predominantly displayed mutant-like behavior. These data suggest that mutant hemichannels may act on cellular homeostasis in a manner that can be detrimental to the tissues in which they are expressed.
authors.affiliation: Dept. of Physiology and Biophysics, State University of New York, T5-147, Basic Science Tower, Stony Brook, NY 11794-8661, USA.
authors.forename: Dwan A
authors.initials: DA
authors.lastname: Gerido
authors.forename: Adam M
authors.initials: AM
authors.lastname: DeRosa
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D003638:Deafness / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015640:Ion Channel Gating / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007634:Keratitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials; D008845:Microinjections; D009154:Mutation; D009865:Oocytes / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013577:Syndrome; D014982:Xenopus laevis
chemical_list: D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; D007473:Ion Channels; D000072259:Connexin 26; D002118:Calcium