title: Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies.
abstract: Connexin 30 (Cx30), a member of the large gap-junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigate the underlying mechanisms of four autosomal dominant Cx30 gene mutations that are linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild-type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to the Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function but did not cause cell death. Lastly, the A88V mutant, which is linked to the development of Clouston syndrome, also significantly induced apoptosis but through an endoplasmic-reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants might cause disease through different mechanisms that also likely include their selective trans-dominant effects on coexpressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.
authors: Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors: Amy C
authors: AC
authors: Berger
authors: John J
authors: JJ
authors: Kelly
authors: Patrick
authors: P
authors: Lajoie
authors: Qing
authors: Q
authors: Shao
authors: Dale W
authors: DW
authors: Laird
mesh_terms: D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D000072259:Connexin 26; D000075302:Connexin 30; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics; D017629:Gap Junctions / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D051381:Rats; D012871:Skin Diseases / Q000235:genetics*
chemical_list: D000075302:Connexin 30; D018031:Connexin 43; D017630:Connexins; C580592:Gja1 protein, rat; C100629:Gjb6 protein, mouse; D000072259:Connexin 26
keywords: Bart-Pumphrey syndrome; Clouston syndrome; Connexin; Gap junction; Hearing loss; Hemichannel; Keratitis-ichthyosis-deafness syndrome; Mutation; Skin disease; Vohwinkel syndrome