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Originally published online as doi:10.2353/ajpath.2008.080049 on September 11, 2008

Published online before print September 11, 2008
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(American Journal of Pathology. 2008;173:1113-1119.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080049

A Novel Missense Mutation in the Second Extracellular Domain of GJB2, p.Ser183Phe, Causes a Syndrome of Focal Palmoplantar Keratoderma with Deafness

Eugene A. de Zwart-Storm*{dagger}{ddagger}, Michel van Geel*{dagger}, Pierre A.F.A. van Neer§, Peter M. Steijlen*{dagger}, Patricia E. Martin{ddagger} and Maurice A.M. van Steensel*{dagger}

From the Department of Dermatology,* University Medical Centre Maastricht, Maastricht, The Netherlands; GROW-School for Oncology and Developmental Biology,{dagger} the Department of Biological and Biomedical Sciences,{ddagger} Glasgow Caledonian University, Glasgow, United Kingdom and the University Maastricht, The Netherlands; the Department of Dermatology,§ Laurentius Hospital, Roermond, The Netherlands

Gap junctions, which consist of connexins, are intercellular channels that mediate rapid intercellular communication. In the skin, connexins are involved in the regulation of epidermal growth and differentiation. GJB2 encodes connexin26, which is an important skin-expressed gap junction protein. Mutations in GJB2 cause a wide variety of unique disorders, but despite extensive research, their mechanisms of action are poorly understood. The identification of novel diseases caused by mutations in GJB2 may help to illuminate the genotype-phenotype correlation and elucidate the function of different regions of the protein. Here, we report the first account of a family with a GJB2 missense mutation in the second extracellular domain (p.Ser183Phe) that causes skin abnormalities in addition to sensorineural hearing loss. Using fluorescent connexin26-EGFP fusion proteins, we showed that the mutation induces a partial protein transport defect that cannot be rescued by wild-type protein. Dye-transfer experiments using a parachute assay revealed channel functionality. Although p.Ser183Phe affects the second extracellular domain, mutations in the first extracellular domain also lead to focal palmoplantar keratoderma and likewise perturb protein transport in a dominant-negative manner. Therefore, we hypothesize that focal palmoplantar keratoderma in gap junction skin disease may be specifically associated with connexin trafficking defects as well as with mutations affecting its extracellular domains, thus broadening the spectrum of GJB2-associated diseases.






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