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:

C1 inhibitor hinge region mutations produce dysfunction by different mechanisms

Nature Genetics volume 1, pages 354–358 (1992)Cite this article

Abstract

Heterozygosity for a mutant dysfunctional C1 inhibitor protein, a member of the serine proteinase inhibitor (serpin) superfamily, results in type II hereditary angioneurotic oedema. We identified a “hinge” region mutation in C1 inhibitor with a Val to Glu replacement at P14 Val–432. Recombinant C1 inhibitors P10 Ala→Thr and P14 Val→Glu did not form stable complexes with fluid phase C1s or kallikrein. The P14 Val→Glu mutant, however, was cleaved to a 96K form by C1s, while the P10 Ala→Thr mutant was not. The recombinant P10 mutant also did not complex with C1s, kallikrein or β–factor XIIa–Sepharose. The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val→Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala→Thr), interaction with target protease is blocked.

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. Carrell, R.W. & Boswell, D.R., Serpins: The superfamily of serine proteinase inhibitors: in Proteinase inhibitors, (eds Barrett, A. & Salvesen, G.) 403–420 (Elsevier, Amsterdam, 1986).

    Google Scholar 

  2. Schechter, J. & Berger, A. Biochem. Biophys. Res. Commun. 27, 157–162 (1967).

    Article  CAS  Google Scholar 

  3. Mathesen, N.R., van Halbeck, H. & Travis, J. J. biol. Chem. 266, 13489–13491 (1991).

    Google Scholar 

  4. Pemberton, P.A., Harrison, R.A., Lachmann, P.J. & Carrell, R.W. Biochem. J. 258, 193–198 (1989).

    Article  CAS  Google Scholar 

  5. Carrell, R.W. & Owen, M.C. Nature 317, 730–732 (1985).

    Article  CAS  Google Scholar 

  6. Pemberton, P.A., Stein, P.E., Pepys, M.B., Potter, J.M. & Carrell, R.W. Nature 336, 257–258 (1988).

    Article  CAS  Google Scholar 

  7. Loebermann, H., Tokuoka, R., Diesenhofer, J. & Huber, R. J. molec. Biol. 177, 531–557 (1984).

    Article  CAS  Google Scholar 

  8. Stein, P.E. et al. Nature 347, 99–102 (1990).

    Article  CAS  Google Scholar 

  9. Carrell, R.W., Evans, D.L. & Stein, P.E. Nature 353, 576–578 (1991).

    Article  CAS  Google Scholar 

  10. Aulak, K.S. et al. Biochem. J. 253, 615–618 (1988).

    Article  CAS  Google Scholar 

  11. Skriver, K., Radziejewska, E., Siebermann, J.A., Donaldson, V.H. & Bock, S.C. J. biol. Chem. 264, 3066–3071 (1989).

    CAS  PubMed  Google Scholar 

  12. Aulak, K.S. & Harrison, R.A. J. 271, 565–569 (1990).

    CAS  Google Scholar 

  13. Devraj-Kizuk, R. et al. Blood 72, 1518–1523 (1988).

    CAS  PubMed  Google Scholar 

  14. Rijken, D.C., Groeneveld, E., Kluft, C. & Nieuwenhuis, H.K. Biochem. J. 255, 609–615 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Perry, D.J., Harper, P.L., Fairham, S., Daly, M. & Carrell, R.W. FEBS Lett. 254, 174–176 (1989).

    Article  CAS  Google Scholar 

  16. Molho-Sabatier, P. et al. J. clin. Invest. 84, 1236–1242 (1989).

    Article  CAS  Google Scholar 

  17. Levy, N.J., Ramesh, N., Cicardi, M., Harrison, R.A. & Davis, III A.E. Proc. natn. Acad. Sci. U.S.A. 87, 265–268 (1990).

    Article  CAS  Google Scholar 

  18. Caso, R. et al. Brit. J. Haem. 77, 87–92 (1991).

    Article  CAS  Google Scholar 

  19. Skriver, K. et al. J. biol. Chem. 266, 9216–9221 (1991).

    CAS  PubMed  Google Scholar 

  20. Aiach, M. et al. Thromb. Res. 39, 559–570 (1985).

    Article  CAS  Google Scholar 

  21. Cugno, M. et al. J. clin. Invest. 85, 1215–1220 (1990).

    Article  CAS  Google Scholar 

  22. Rosen, F.S., Alper, C.A., Pensky, J., Klemperer, M.R. & Donaldson, V.H. J. clin. Invest. 50, 2143–2149 (1971).

    Article  CAS  Google Scholar 

  23. Donaldson, V.H. et al. Blood 69, 1096–1101 (1987).

    CAS  PubMed  Google Scholar 

  24. Donaldson, V.H. et al. J. clin. Invest. 75, 124–132 (1985).

    Article  CAS  Google Scholar 

  25. Harrison, R.A. Biochemistry 22, 5001–5007 (1983).

    Article  CAS  Google Scholar 

  26. Laemmli, U.K. Nature 227, 680–685 (1970).

    Article  CAS  Google Scholar 

  27. Bing, D.H., Andrews, J.M., Morris, K.M., Cole, E. & Irish, V. Prep. Biochem. 10, 269–296 (1980).

    CAS  PubMed  Google Scholar 

  28. Einstein, L.P., Schneeberger, E.E. & Colten, H.R. J. exp. Med. 143, 114–126 (1976).

    Article  CAS  Google Scholar 

  29. Chirgwin, J.M., Przbyla, A.E., MacDonald, R.J. & Rutter, W.J. Biochemistry 18, 5294–5299 (1979).

    Article  CAS  Google Scholar 

  30. Bock, S.C. et al. Biochemistry 25, 4292–4301 (1986).

    Article  CAS  Google Scholar 

  31. Sanger, F., Nicklen, S. & Coulson, R.A. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    Article  CAS  Google Scholar 

  32. Katz, Y. & Strunk, R.C. J. Immunol. 142, 2041–2045 (1989).

    CAS  PubMed  Google Scholar 

  33. Cole, F.S., Auerbach, H.S., Goldberg, G. & Colten, H.R. J. Immunol. 134, 2610–2616 (1985).

    CAS  PubMed  Google Scholar 

  34. Eldering, E., Nuijens, J.H. & Hack, C.E. J. biol. Chem. 263, 11776–11779 (1988).

    CAS  PubMed  Google Scholar 

  35. Luthmann, H. & Magnusson, G. Nucleic Acids Res. 5, 1295–1308 (1983).

    Article  Google Scholar 

  36. Nuijens, J.H., Huijbregts, C.C.M., van Mierlo, G.M. & Hack, C.E. mmunology 61, 387–389 (1987).

    CAS  Google Scholar 

  37. Harrison, R.A. & Rosen, F.S. Molec. Immunol. 19, 1374 (abstract) (1982).

    Article  Google Scholar 

  38. Holmes, W.E. et al. Science 238, 209–211 (1987).

    Article  CAS  Google Scholar 

  39. Parad, R.B., Kramer, J., Strunk, R.C., Rosen, F.S. & Davis, III A.E. Proc. natn. Acad. Sci. U.S.A. 87, 6786–6790 (1990).

    Article  CAS  Google Scholar 

  40. Roos, M.H., Mollenhauer, E., Demant, P. & Rittner, C. Nature 298, 854–856 (1982).

    Article  CAS  Google Scholar 

  41. Carroll, M.C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 6868–6872 (1990).

    Article  CAS  Google Scholar 

  42. de Agostini, A. et al. J. clin. Invest. 82, 700–705 (1988).

    Article  CAS  Google Scholar 

  43. Engh, R.A., Wright, H.T. & Huber, R. Protein Engineering 3, 369–477 (1990).

    Google Scholar 

  44. Mottonen, J. et al. Nature 355, 270–273 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Fred S. Rosen

    Present address: National Institute of Haematology and Blood Transfusion, Budapest, Hungary

Authors and Affiliations

  1. Division of Nephrology, Children's Hospital Research Foundation, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA

    Alvin E. Davis III, Kulwant Aulak & John Bissler

  2. Joint Program in Neonatology, The Children's Hospital, Boston, Massachusetts, 02115, USA

    Richard B. Parad

  3. Division of Nephrology, The Children's Hospital, Boston, Massachusetts, 02115, USA

    Hilary P. Stecklein

  4. Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands

    Eric Eldering & C. Erik Hack

  5. Department of Pediatrics, Washington University Medical School, St. Louis, Missouri, 63110, USA

    Judit Kramer & Robert C. Strunk

  6. The Center for Blood Research, Boston, Massachusetts, 02115, USA

    Judit Kramer

Authors
  1. Alvin E. Davis III
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kulwant Aulak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard B. Parad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilary P. Stecklein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric Eldering
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Erik Hack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Judit Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert C. Strunk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John Bissler
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fred S. Rosen
    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

Davis, A., Aulak, K., Parad, R. et al. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet 1, 354–358 (1992). https://doi.org/10.1038/ng0892-354

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0892-354

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