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.

  • Article
  • Published:

A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa

Nature Genetics volume 4, pages 62–66 (1993)Cite this article

Abstract

Recessive dystrophic epidermolysis bullosa is a severe mutilating genodermatosis. Previous ultrastructural demonstrations of altered anchoring fibrils, and recent genetic linkage analyses have suggested that type VII collagen, the major component of anchoring fibrils, is a candidate gene. We have identified a homozygous methionine–to–lysine mutation in two affected siblings, while their unaffected mother and half–brother are heterozygous carriers. The mutation resides in a highly conserved region of the C–terminus of type VII collagen, strongly suggesting that it is the cause of the disease in this family.

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

Similar content being viewed by others

References

  1. Fine, J.D. et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the subcommittee on diagnosis and classification of the national epidermolysis bullosa registry. J. Am. Acad. Dermatol. 24, 119–135 (1991).

    Article  CAS  Google Scholar 

  2. Lin, A.N. & Carter, D.M. (eds) Epidermolysis bullosa. Basic and clinical aspects. (Springer, New York, 1992).

    Book  Google Scholar 

  3. Uitto, J. & Christiano, A.M. Molecular genetics of the cutaneous basement membrane zone. Perspectives on epidermolysis bullosa and other blistering skin diseases. J. clin. Invest. 90, 687–692 (1992).

    Article  CAS  Google Scholar 

  4. Fuchs, E. & Coulombe, P.A. Of mice and men: genetic skin diseases of keratin. Cell 69, 899–902 (1992).

    Article  CAS  Google Scholar 

  5. Epstein, E.H., Jr. Molecular genetics of epidermolysis bullosa. Science 256, 799–804 (1992).

    Article  CAS  Google Scholar 

  6. Bonifas, J.M., Rothman, A.L. & Epstein, E.H., Jr. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254, 1202–1205 (1991).

    Article  CAS  Google Scholar 

  7. Coulombe, P.A. et al. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and funtional analyses. Cell 66, 1301–1311 (1991).

    Article  CAS  Google Scholar 

  8. Lane, E.B. et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 356, 244–246 (1992).

    Article  CAS  Google Scholar 

  9. Rothnagel, J.A. et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 257, 1128–1130 (1992).

    Article  CAS  Google Scholar 

  10. Cheng, J. et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin gene. Cell 70, 811–819 (1992).

    Article  CAS  Google Scholar 

  11. Chipev, C.C. et al. A leucine → proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 70, 821–828 (1992).

    Article  CAS  Google Scholar 

  12. Coulombe, P.A., Hutton, M.E., Vassar, R. & Fuchs, E. A function of keratins and a common thread among different types of epidermolysis bullosa simplex diseases. J. cell Biol. 115, 1661–1674 (1991).

    Article  CAS  Google Scholar 

  13. Fuchs, E., Esteves, R.A. & Coulombe, P.A. Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis. Proc. natn. Acad. Sci. U.S.A. 89, 6906–6910 (1992).

    Article  CAS  Google Scholar 

  14. Tidman, M.J. & Eady, R.A.J. Evaluation of anchoring fibrils and other components of the dermal-epidermal junction in dystrophic epidermolysis bullosa by a quantitative ultrastructural technique. J. invest. Dermatol. 84, 374–377 (1985).

    Article  CAS  Google Scholar 

  15. Bruckner-Tuderman, L. Collagens of the dermo-epidermal junction: role in bullous disorders. Eur. J. Dermatol. 1, 89–100 (1991).

    Google Scholar 

  16. Burgeson, R.E. et al. The structure and function of type VII collagen. Ann. N.Y. Acad. Sci. 580, 32–43 (1990).

    Article  CAS  Google Scholar 

  17. Uitto, J., Chung-Honet, L.C. & Christiano, A.M. Molecular biology and pathology of type VII collagen. Exp. Dermatol. 1, 2–11 (1992).

    Article  CAS  Google Scholar 

  18. Ryynänen, M. et al. Human type VII collagen: genetic linkage of the gene (COL7A1) on chromosome 3 to dominant dystrophic epidermolysis bullosa. Am. J. hum. Genet. 49, 797–803 (1991).

    PubMed  PubMed Central  Google Scholar 

  19. Ryynänen, M. et al. Genetic linkage of type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils. J. clin. Invest. 89, 974–980 (1992).

    Article  Google Scholar 

  20. Gruis, N.A. et al. Genetic linkage between the collagen VII (COL7A1) gene and the autosomal dominant form of dystrophic epidermolysis bullosa in two Dutch kindreds. J. invest. Dermatol. 99, 528–530 (1992).

    Article  CAS  Google Scholar 

  21. Al-Imara, L. et al. Linkage of autosomal dominant dystophic epidermolysis bullosa in three British families to the marker D3S2 close to the COL7A1 locus. J. med. Genet. 29, 381–382 (1992).

    Article  CAS  Google Scholar 

  22. Hovnanian, A. et al. Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene. J. clin. Invest. 90, 1038–1046 (1992).

    Article  Google Scholar 

  23. Parente, M.G. et al. Human type VII collagen: cDNA cloning and chromosomal mapping of the gene. Proc. natn. Acad. Sci. U.S.A. 88, 6931–6935 (1991).

    Article  CAS  Google Scholar 

  24. Greenspan, D.S., Byers, M.G., Eddy, R.L., Hoffman, G.G. & Shows, T.B. Localization of the human collagen gene COL7A1 to 3p21.3 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 62, 35–36 (1993).

    Article  CAS  Google Scholar 

  25. Christiano, A.M. et al. The large non-collagenous domain (NC-1) of type VII collagen is amino-terminal and chimeric. Homology to cartilage matrix protein, the type III domains of fibronectin and the A domains of von Willebrand factor. Human molec. Genet. 1, 475–481 (1992).

    Article  CAS  Google Scholar 

  26. Ryynänen, J., et al. Type VII collagen gene expression by cultured human cells and in fetal skin. Abundant mRNA and protein levels in epidermal keratinocytes. J. clin. Invest. 89, 163–168 (1992).

    Article  Google Scholar 

  27. Greenspan, D.S. et al. The carboxyl-terminal half of type VII collagen, including the non-collagenous NC-2 domain and intron/exon organization of the corresponding region of the COL7A1 gene. Human molec. Genet. 2, 273–278 (1993).

    Article  CAS  Google Scholar 

  28. Li, K. et al. cDNA cloning and chromosomal mapping of the mouse type VII collagen gene (COL7A1). Genomics (in the press).

  29. Christiano, A.M., Chung-Honet, L.C., Hovnanian, A. & Uitto, J. PCR-based detection of two exonic polymorphisms in the human type VII collagen gene (COL7A1) at 3p21.1. Genomics 14, 827–828 (1992).

    Article  CAS  Google Scholar 

  30. Kuivaniemi, H., Tromp, G. & Prockop, D.J. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J. 5, 2052–2060 (1991).

    Article  CAS  Google Scholar 

  31. Prockop, D.J. Mutations in collagen genes as a cause of connective-tissue diseases. New Engl. J. Med. 326, 540–546 (1992).

    Article  CAS  Google Scholar 

  32. Hovnanian, A. et al. A missennse mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex. Nature Genet. 3, 327–332 (1993).

    Article  CAS  Google Scholar 

  33. Booth, B.A., Polak, K.L. & Uitto, J. Collagen biosynthesis by human skin fibroblasts. I. Optimization of the culture conditions for synthesis of type I and type III procollagens. Biochim. Biophys. Acta 607, 145–160 (1980).

    Article  CAS  Google Scholar 

  34. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  35. Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Jefferson Medical College, Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA

    Angela M. Christiano, Xin Zhang, Yoshiko Tamai & Jouni Uitto

  2. Departments of Biochemistry and Molecular Biology, Jefferson Medical College, Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA

    Jouni Uitto

  3. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, 53706, USA

    Daniel S. Greenspan & Guy G. Hoffman

  4. Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, 10021, USA

    Andrew N. Lin

  5. Departments of Pediatric Cardiology and Medical Genetics, Johns Hopkins University Medical School, Baltimore, Maryland, USA

    Harry C. Dietz

  6. Laboratory of Molecular Genetics, INSERM U91, H. Mondor Hospital, 94010, Creteil, France

    Alain Hovnanian

Authors
  1. Angela M. Christiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel S. Greenspan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy G. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiko Tamai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew N. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harry C. Dietz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alain Hovnanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jouni Uitto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christiano, A., Greenspan, D., Hoffman, G. et al. A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa. Nat Genet 4, 62–66 (1993). https://doi.org/10.1038/ng0593-62

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0593-62

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