Journal Article

A Missense Mutation in Connexin26, D66H, Causes Mutilating Keratoderma with Sensorineural Deafness (Vohwinkel's Syndrome) in Three Unrelated Families

Elena Maestrini, Bernhard P. Korge, Juan Ocaña-Sierra, Elisa Calzolari, Stefano Cambiaghi, Pat M. Scudder, Alain Hovnanian, Anthony P. Monaco and Colin S. Munro

in Human Molecular Genetics

Volume 8, issue 7, pages 1237-1243
Published in print July 1999 | ISSN: 0964-6906
Published online July 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.7.1237
A Missense Mutation in Connexin26, D66H, Causes Mutilating Keratoderma with Sensorineural Deafness (Vohwinkel's Syndrome) in Three Unrelated Families

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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 (C×26) gene (GJB2) at 13q11–q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominantdeaf-ness (DFNA3). We now report a C×26 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 C×26 locus. All 10 affected members were heterozygous for a non-conservative mutation, D66H, in C×26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in C×26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the C×26 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 C×26 can impair epidermal differentiation, as well as inner ear function.

Journal Article.  4160 words.  Illustrated.

Subjects: Genetics and Genomics

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