MUTATIONS IN THE HUMAN CONNEXIN GENE GJB3 CAUSE ERYTHROKERATODERMIA VARIABILIS

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal domi nant genodermatosis with considerable intra- and interfamilial variabi lity(1). It has a disfiguring phenotype characterized by the independe nt occurrence of two morphologic features: transient figurate red patc hes and localized or generalized hyperkeratosis (Fig. 1). Both feature s can be triggered by external factors such as trauma to the skin. Aft er initial linkage to the RH locus on 1p (refs 2,3). EKV was mapped to an an interval of 2.6 cM on 1p34-p35. and a candidate gene (GJA4) enc oding the gap junction protein alpha-4 (connexin 31. Cx31) was exclude d by sequence analysis(4). Evidence in mouse suggesting that the EKV r egion harbours a cluster of epidermally expressed connexin genes(5,6) led us to characterize the human homologues of GJB3 (encoding Cx31) an d GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1- Mb YAC in the candidate interval. We detected heterozygous missense mu tations in GJB3 in four EKV families leading to substitution of a cons erved glycine by charged residues (G12R and G12D). or change of a cyst eine (C865). These mutations are predicted to interfere with normal Cx 31 structure and function, possibly due to a dominant inhibitory effec t. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.