A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families

The multiplicity of functions served by intercellular gap junctions is refl ected by the variety of phenotypes caused by mutations in the connexins of which they are composed. Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), bu t have also been reported in autosomal dominant deafness (DFNA3), We now re port a Cx26 mutation in three families with mutilating keratoderma and deaf ness [Vohwinkel's syndrome (VS; MIM 124500), as originally described], VS i s characterized by papular and honeycomb keratoderma associated with constr ictions of digits leading to autoamputation, distinctive starfish-like acra l keratoses and moderate degrees of deafness. In a large British pedigree, we have mapped the defect to the Cx26 locus. All 10 affected members were h eterozygous for a nonconservative mutation, D66H, in Cx26. The same mutatio n was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a co mmon mutation in classical VS. This mutation occurs at a highly conserved r esidue in the first extracellular domain of the Cx26 molecule, and may exer t its effects by interfering with assembly into connexons, docking with adj acent cells or gating properties of the gap junction. Our results provide e vidence that a specific mutation in Cx26 can impair epidermal differentiati on, as well as inner ear function.