Human Molecular Genetics, 1999, Vol. 8, No. 7 1237-1243
© 1999 Oxford University Press
A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families
1Wellcome Trust Centre for Human Genetics, University of Oxford, Windmill Road, Oxford OX3 7BN, UK, 2Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, Germany, 3Catedra de Dermatologia, Universidad de Granada, Avenida de Madrid 11, 18012 Granada, Spain, 4Istituto di Genetica Medica, Dipartimento di Medicina Sperimentale e Diagnostica, Ferrara, Italy, 5Istituto di Scienze Dermatologiche, IRCCS, Università di Milano, Italy and 6Department of Dermatology, Southern General Hospital, Glasgow G51 4TF, UK
The multiplicity of functions served by intercellular gap junctions is reflected 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), but have also been reported in autosomal dominant deafness (DFNA3). We now report a Cx26 mutation in three families with mutilating keratoderma and deafness [Vohwinkel’s syndrome (VS; MIM 124500), as originally described]. VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral 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 heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function.
a To whom correspondence should be addressed. Tel: +44 1865 740021; Fax: +44 1865 742186; Email: maestrin{at}well.ox.ac.uk
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