A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness

Eugene A. de Zwart-Storm ¹, Henning Hamm ², Johanna Stoevesandt ², Patricia Martin ³, Peter M Steijlen ¹, Michel van Geel ¹ and Maurice A.M. van Steensel ^1*

¹ University Hospital Maastricht, Netherlands
² University of Würzburg, Germany
³ Glasgow Caledonian University, United Kingdom

^* To whom correspondence should be addressed. E-mail: mauricevansteensel{at}mac.com.

Accepted 19 October 2007

Abstract

Gap junctions are intercellular channels that mediate rapid intercellular communication. They consist of connexins, small transmembrane proteins that belong to a large family found throughout the animal kingdom. In the skin, several connexins are expressed and are involved in the regulation of epidermal growth and differentiation. One of the skin expressed gap junction genes is GJB2, which codes for connexin 26 and is associated with a wide variety of keratinisation disorders. Here, we report on a family with a novel GJB2 mutation (p.His73Arg) causing a syndrome of focal palmoplantar keratoderma with severe progressive sensorineural hearing impairment, a phenotype reminiscent of Vohwinkel syndrome. Using fluorescent connexin fusion proteins, we show that the mutation induces a transport defect similar to that found for the Vohwinkel syndrome mutation p.Asp66His. Co-transfection with wild type connexin30 and connexin26 shows that the mutant has a dominant negative effect on connexin trafficking. We suggest that there may be a weak genotype-phenotype correlation for mutations in GJB2.

Keywords: connexin26, deafness, gap junction, palmoplantar keratoderma

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• de Zwart-Storm, E. A., van Geel, M., van Neer, P. A.F.A., Steijlen, P. M., Martin, P. E., van Steensel, M. A.M. (2008). A Novel Missense Mutation in the Second Extracellular Domain of GJB2, p.Ser183Phe, Causes a Syndrome of Focal Palmoplantar Keratoderma with Deafness. Am. J. Pathol. 173: 1113-1119 [Abstract] [Full Text]