Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis

Nature Genetics volume 20, pages 366–369 (1998)Cite this article

Abstract

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 α-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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical features of EKV.
Figure 2: Schematic of human Cx31 showing coding sequence, predicted structural motifs and the newly identified Cx31 mutations in EKV.
Figure 3: GJB3 mutations in EKV.
Figure 4: Sequence comparisons.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Mendes da Costa, S. Erythro- et keratodermia variabilis in a mother and a daughter. Acta Derm. Venereol. 6, 255–261 (1925).

    Google Scholar 

  2. van der Schroeff, J.G. et al. Genetic linkage between erythrokeratodermia variabilis and Rh locus. Hum. Genet. 68, 165– 168 (1984).

    Article  CAS  Google Scholar 

  3. van der Schroeff, J.G., van Leeuwen-Cornelisse, I., van Haeringen, A. & Went, L.N. Further evidence for localization of the gene of erythrokeratodermia variabilis. Hum. Genet. 80, 97–98 (1988).

    Article  CAS  Google Scholar 

  4. Richard, G. et al. Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J. Invest. Dermatol . 109, 666–671 ( 1997).

    Article  CAS  Google Scholar 

  5. Haefliger, J.A. et al. Four novel members of the connexin family of gap junction proteins. Molecular cloning, expression, and chromosome mapping. J. Biol. Chem. 267, 2057–2064 (1992).

    CAS  PubMed  Google Scholar 

  6. Hennemann, H. et al. Two gap junction genes, connexin 31.1 and 30.3, are closely linked on mouse chromosome 4 and preferentially expressed in skin. J. Biol. Chem. 267, 17225–17233 (1992).

    CAS  PubMed  Google Scholar 

  7. Bruzzone, R., White, T.W. & Paul, D.L. Connections with connexins: the molecular basis of direct intercellular signaling. Eur. J. Biochem. 238, 1–27 (1996).

    Article  CAS  Google Scholar 

  8. Goodenough, D.A., Goliger, J.A. & Paul, D.L. Connexins, connexons, and intercellular communication. Annu. Rev. Biochem. 65, 475– 502 (1996).

    Article  CAS  Google Scholar 

  9. Goliger, J.A. & Paul, D.L. Expression of gap junction proteins cx26, cx31.1, cx37, and cx43 in developing and mature rat epidermis. Dev. Dyn. 200, 1–13 ( 1994).

    Article  CAS  Google Scholar 

  10. Butterweck, A., Elfgang, K., Willeke, K. & Traub, O. Differential expression of the gap junction proteins connexin45, -43, -40, -31, and -26 in mouse skin. Eur. J. Cell. Biol. 65, 152– 163 (1994).

    CAS  PubMed  Google Scholar 

  11. Risek, B., Klier, F.G. & Gilula, N.B. Multiple gap junction are utilized during rat skin and hair development. Development 116, 639 –651 (1992).

    CAS  PubMed  Google Scholar 

  12. Brissette, J.L., Kumar, N.M., Gilula, N.B., Hall, J.E. & Dotto, G.P. Switch in gap junction protein expression is associated with selective changes in junctional permeability during keratinocyte differentiation. Proc. Natl Acad. Sci. USA 91, 6453–6457 (1994).

    Article  CAS  Google Scholar 

  13. Guo, H., Acevedo, P., Parsa, F.D. & Bertram, J.S. Gap-junctional protein connexin 43 is expressed in dermis and epidermis of human skin: differential modulation by retinoids. J. Invest. Dermatol. 99, 460–467 (1992).

    Article  CAS  Google Scholar 

  14. Masgrau-Peya, E., Salomon, D., Saurat, J.H. & Meda, P. In vivo modulation of connexins 43 and 26 of human epidermis by topical retinoic acid treatment. J. Histochem. Cytochem. 45 , 1207–1215 (1997).

    Article  CAS  Google Scholar 

  15. Larson, D.M., Wrobleski, M.J., Sagar, G.D., Westphale, E.M. & Beyer, E.C. Differential regulation of connexin 43 and connexin 37 in endothelial cells by cell density, growth, and TGF-β1. Am. J. Physiol. 272, C405– 415 (1997).

    Article  CAS  Google Scholar 

  16. Reed, K.E. et al. Molecular cloning and functional expression of human connexin 37, an endothelial cell gap junction protein. J. Clin. Invest. 91, 997–1004 ( 1993).

    Article  CAS  Google Scholar 

  17. Hoh, J.H., John, S.A. & Revel, J.P. Molecular cloning and characterization of a new member of the gap junction gene family, connexin-31. J. Biol. Chem. 266, 6524–6531 (1991).

    CAS  PubMed  Google Scholar 

  18. Hennemann, H., Schwarz, H.J. & Willecke, K. Characterization of gap junction genes expressed in F9 embryonic carcinoma cells: molecular cloning of mouse connexin31 and -45 cDNAs. Eur. J. Cell Biol. 57, 51– 58 (1992).

    CAS  PubMed  Google Scholar 

  19. Yeager, M. & Nicholson, B.J. Structure of gap junction intercellular channels. Curr. Opin. Struct. Biol. 6, 183 –192 (1996).

    Article  CAS  Google Scholar 

  20. Bergoffen, J. et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262, 2039–2042 (1993).

    Article  CAS  Google Scholar 

  21. Kelsell, D.P. et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387, 80– 83 (1997).

    Article  CAS  Google Scholar 

  22. Shiels, A., Mackay, D., Ionides, A., Berry, V. & Moore, A. A missense mutation in the human connexin 50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q. Am. J. Hum. Genet. 62, 526– 532 (1998).

    Article  CAS  Google Scholar 

  23. Verselis, V.K., Ginter, C.S. & Bargiello, T.A. Opposite voltage gating polarities of two closely related connexins. Nature 368, 348– 351 (1994).

    Article  CAS  Google Scholar 

  24. Denoyelle, F. et al. Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum. Mol. Genet. 6, 2173–2177 (1997).

    Article  CAS  Google Scholar 

  25. Zelante, L. et al. Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum. Mol. Genet. 6, 1605– 1609 (1997).

    Article  CAS  Google Scholar 

  26. Deschênes, M. et al. Altered trafficking of mutant connexin 32. J. Neuroscience 17, 9077–9084 ( 1997).

    Article  Google Scholar 

  27. Suchyna, T.M., Xu, L.X., Gao, F., Fourtner, C.R. & Nicholson, B.J. Identification of a proline residue as a transduction element involved in voltage gating of gap junctions. Nature 365, 847–849 (1993).

    Article  CAS  Google Scholar 

  28. Krawczak M. & Cooper D.N. The human gene mutation database. Trends Genet. 13, 121– 122 (1997).

    Article  CAS  Google Scholar 

  29. Richards, B. et al. Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs. Hum. Mol. Genet. 2, 159–163 (1993).

    Article  CAS  Google Scholar 

  30. Itin, P., Levy, C.A., Sommacal-Schopf, D. & Schnyder, U.W. Family study of erythrokeratodermia figurata variabilis. Hautarzt 43, 500–504 ( 1992).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the families for their generous participation in our studies, and to the Foundation for Ichthyosis and Related Skin Types and the National Registry for Ichthyosis for patient referral. We also appreciate the expert research nursing assistance by M. Miller and M. Anderson, and outstanding technical services of G. Poy in oligonucleotide synthesis and DNA sequencing. D.H. and P.I. were supported by the Swiss National Science Foundation.

Author information

Authors and Affiliations

  1. Genetic Studies Section, Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Gabriele Richard, Lisa E. Smith, Regina A. Bailey, John J. DiGiovanna, John G. Compton & Sherri J. Bale.

  2. Department of Dermatology, University of Basel, Switzerland

    Peter Itin

  3. Department of Dermatology, Hôspital Beaumont, Lausanne, Switzerland

    Daniel Hohl

  4. Department of Dermatology, San Francisco General Hospital, University of California, San Francisco, California, USA

    Ervin H. Epstein Jr

  5. Division of Dermatopharmacology, Department of Dermatology, Brown University, Rhode Island Hospital, Providence, Rhode Island, USA

    John J. DiGiovanna

Authors
  1. Gabriele Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa E. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Regina A. Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Itin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Hohl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ervin H. Epstein Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John J. DiGiovanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John G. Compton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sherri J. Bale.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gabriele Richard or Sherri J. Bale..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Richard, G., Smith, L., Bailey, R. et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 20, 366–369 (1998). https://doi.org/10.1038/3840

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/3840

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing