A heterozygous mutation in GJB2 (Cx26F142L) associated with deafness and recurrent skin rashes results in connexin assembly deficiencies.

Albuloushi, Ahmad, Lovgren, Marie-Louise, Steel, Ainsley, Yeoh, Yeelon, Waters, Alex, Zamiri, Mozheh and Martin, Patricia E (2020) A heterozygous mutation in GJB2 (Cx26F142L) associated with deafness and recurrent skin rashes results in connexin assembly deficiencies. Experimental dermatology. ISSN 1600-0625. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://onlinelibrary.wiley.com/doi/10.1111/exd.14...

Abstract

Mutations in GJB2 encoding Connexin 26 (CX26) are associated with hearing loss and hyperproliferative skin disorders of differing severity including keratitis-ichthyosis-deafness (KID) and Vohwinkel syndrome. A 6-year-old Caucasian girl who presented with recurrent skin rashes and sensorineural hearing loss harboured a heterozygous point mutation in GJB2 (c.424T > C; p.F142L). To characterize the impact of CX26F142L on cellular events. Plasmids CX26WT, CX26F142L, CX26G12R (KID) or CX26D66H (Vohwinkel) were transfected into HeLa cells expressing Cx26 or Cx43 or into HaCaT cells, a model keratinocyte cell line. Confocal microscopy determined protein localization. MTT assays assessed cell viability in the presence or absence of carbenoxolone, a connexin-channel blocker. Co-immunoprecipitation/Western blot analysis determined Cx43:Cx26 interactions. Quantitative real-time polymerase chain reaction assessed changes in gene expression of ER stress markers. Dye uptake assays determined Connexin-channel functionality. F142L and G12R were restricted to perinuclear areas. Collapse of the microtubule network, rescued by co-treatment with paclitaxel, occurred. ER stress was not involved. Cell viability was reduced in cells expressing F142L and G12R but not D66H. Unlike G12R that forms "leaky" hemichannels, F142L had restricted permeability. Cell viability of F142L and G12R transfected cells was greater in HeLa cells expressing Cx43 than in native Cx-free HeLa cells. Co-immunoprecipitation suggested a possible interaction between Cx43 and the three mutations. Expression of CX26F142L and G12R results in microtubule collapse, rescued by interaction with Cx43. The GJB2 mutations interacted with Cx43 suggesting that unique Cx43:Cx26 channels are central to the diverse phenotype of CX26 skin-related channelopathies.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: WR Skin. Dermatology
WV Otorhinolaryngology. ENT medicine
Divisions: Ambulatory Care > Dermatology
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Depositing User: Mrs Yolande Brookes
Date Deposited: 02 Oct 2020 14:08
Last Modified: 02 Oct 2020 14:15
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3501

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