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Human Molecular Genetics, 2003, Vol. 12, No. 14 1737-1744
DOI: 10.1093/hmg/ddg183
© 2003 Oxford University Press

Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders

George Bakirtzis1, Rukhsana Choudhry1, Trond Aasen1, Leonard Shore2, Ken Brown2, Sheila Bryson2, Stephen Forrow2, Laurence Tetley3, Malcolm Finbow4, David Greenhalgh1 and Malcolm Hodgins1,*

1Section of Squamous Cell Biology and Dermatology, Division of Cancer Sciences and Molecular Pathology, Robertson Building, University of Glasgow, Glasgow G12 8QQ, UK, 2Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, UK, 3Electron Microscopy Unit, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK and 4Division of Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK

Received February 24, 2003; Revised May 7, 2003; Accepted May 14, 2003

To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

* To whom correspondence should be addressed. Email: m.b.hodgins{at}clinmed.gla.ac.uk


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