The spectrum of mutations in erythrokeratodermias - novel and de novo mutations in GJB3

Intercellular channels in skin are a complex and functionally diverse syste m formed by at least eight connexins (Cx). Our recent molecular studies imp licating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermi a variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localize d erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently w e identified the causative gene GJB3 encoding Cx31. We have now investigate d GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation lead ing to substitution of a conserved phenylalanine (F137L) in the third trans membrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R4 2P) co-segregated with the disease, while a 12 bp deletion predicted to eli minate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffe cted controls. Including the previously published mutations, in tote, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytopla smic amino terminal and transmembrane domains of Cx31. In contrast, two mut ations linked to progressive high-tone hearing impairment were located in t he second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include pr ogressive symmetric erythrokeratodermia, another dominant genodermatosis wi th overlapping features, since no mutations were found in six unrelated fam ilies tested.