title: EKV mutant connexin 31 associated cell death is mediated by ER stress.
abstract: The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations. The Cx31 mutants (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 are associated with EKV and the mutant (66delD)Cx31 with peripheral neuropathy and hearing loss, however the mechanisms of pathogenesis remain to be elucidated. Expression of (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 in vitro, but not (WT)Cx31 or (66delD)Cx31, cause elevated levels of cell-type specific cell death. Previous studies suggest that Cx-associated cell death may be related to abnormal 'leaky' hemichannels but we produced direct evidence against that being the major mechanism. Additionally, our immunocytochemistry showed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not (WT)Cx31 or (66delD)Cx31. We conclude that the endoplasmic reticulum (ER) stress leading to the UPR is the main mechanism of mutant Cx31-associated cell death. These results indicate that, in vivo, ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin.
authors.affiliation: Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tattersall
authors.forename: Claire A
authors.initials: CA
authors.lastname: Scott
authors.forename: Colin
authors.initials: C
authors.lastname: Gray
authors.forename: Daniel
authors.initials: D
authors.lastname: Zicha
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002450:Cell Communication; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D012871:Skin Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D017630:Connexins; C068044:GJB3 protein, human; D046988:Proteasome Endopeptidase Complex