Nature Genetics
20, 366 - 369 (1998)
doi:10.1038/3840
Mutations in the human connexin gene GJB3 cause erythrokeratodermia
variabilisGabriele Richard1, Lisa E. Smith1, Regina A. Bailey1, Peter Itin2, Daniel Hohl3, Ervin H. Epstein Jr4, John J. DiGiovanna1, 5, John G. Compton1
& Sherri J. Bale.11
Genetic Studies Section, Laboratory of Skin Biology,
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health, Bethesda, Maryland, USA. 2
Department of Dermatology, University of Basel,
Switzerland. 3
Department of Dermatology, Hôspital Beaumont,
Lausanne, Switzerland. 4
Department of Dermatology, San Francisco General Hospital,
University of California, San Francisco, California, USA. 5
Division of Dermatopharmacology, Department of Dermatology,
Brown University, Rhode Island Hospital, Providence,
Rhode Island, USA.
Correspondence should be addressed to Sherri J. Bale. sherrib@box-s.nih.gov or Gabriele Richard Gabriele.Richard@mail.tju.edu
Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant
genodermatosis with considerable intra- and interfamilial variability1. It has a disfiguring phenotype characterized by the independent
occurrence of two morphologic features: transient figurate red patches and
localized or generalized hyperkeratosis (Fig. 1). Both
features can be triggered by external factors such as trauma to the skin.
After initial linkage to the RH locus on 1p (Refs 2,3), EKV was mapped to an interval of 2.6 cM on 1p34-p35,
and a candidate gene (GJA4) encoding the gap junction protein  -4
(connexin 31, Cx31) was excluded by sequence analysis4. Evidence
in mouse suggesting that the EKV region harbours a cluster of epidermally
expressed connexin genes5,
6 led us to characterize the human
homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1).
GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the
candidate interval. We detected heterozygous missense mutations in GJB3
in four EKV families leading to substitution of a conserved glycine by
charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations
are predicted to interfere with normal Cx31 structure and function, possibly
due to a dominant inhibitory effect. 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.
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