Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Apr 1;89(7):2869–2872. doi: 10.1073/pnas.89.7.2869

Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets.

K A Cooney 1, S E Lyons 1, D Ginsburg 1
PMCID: PMC48764  PMID: 1557393

Abstract

Type IIB von Willebrand disease is an autosomal dominant bleeding disorder characterized by the selective loss of high molecular weight von Willebrand factor (vWF) multimers in plasma, presumably due to their abnormally increased reactivity with platelets. We and others have recently identified a panel of missense mutations clustered in the platelet glycoprotein Ib binding domain of vWF from patients with type IIB von Willebrand disease. We now report functional analysis of one of the most frequent type IIB missense mutations, Arg-543----Trp (vWF R543W). vWF from a human umbilical vein endothelial cell culture heterozygous for the vWF R543W mutation showed markedly increased binding of large vWF multimers to platelets in the presence of a low dose of ristocetin compared to vWF from a normal control culture. Recombinant vWF containing the vWF R543W mutation expressed in COS-7 cells also demonstrated increased binding of large vWF multimers. Mixed multimers obtained by cotransfection of mutant and wild-type cDNAs showed partial dominance of the vWF R543W mutation. Thus these data demonstrate that the vWF R543W mutation alone is sufficient to confer increased binding of large vWF multimers to platelets in a dominant fashion and that no other factors relating to vWF posttranslational processing or secretion in endothelial cells are required for this effect.

Full text

PDF
2869

Images in this article

2871Image
on p.2871
2871Image
on p.2871

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cacheris P. M., Nichols W. C., Ginsburg D. Molecular characterization of a unique von Willebrand disease variant. A novel mutation affecting von Willebrand factor/factor VIII interaction. J Biol Chem. 1991 Jul 25;266(21):13499–13502. [PubMed] [Google Scholar]
  2. Coller B. S., Peerschke E. I., Scudder L. E., Sullivan C. A. Studies with a murine monoclonal antibody that abolishes ristocetin-induced binding of von Willebrand factor to platelets: additional evidence in support of GPIb as a platelet receptor for von Willebrand factor. Blood. 1983 Jan;61(1):99–110. [PubMed] [Google Scholar]
  3. Cooney K. A., Nichols W. C., Bruck M. E., Bahou W. F., Shapiro A. D., Bowie E. J., Gralnick H. R., Ginsburg D. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest. 1991 Apr;87(4):1227–1233. doi: 10.1172/JCI115123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De Marco L., Girolami A., Russell S., Ruggeri Z. M. Interaction of asialo von Willebrand factor with glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and mediates platelet aggregation. J Clin Invest. 1985 Apr;75(4):1198–1203. doi: 10.1172/JCI111816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Marco L., Girolami A., Zimmerman T. S., Ruggeri Z. M. Interaction of purified type IIB von Willebrand factor with the platelet membrane glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and initiates aggregation. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7424–7428. doi: 10.1073/pnas.82.21.7424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De Marco L., Mazzucato M., De Roia D., Casonato A., Federici A. B., Girolami A., Ruggeri Z. M. Distinct abnormalities in the interaction of purified types IIA and IIB von Willebrand factor with the two platelet binding sites, glycoprotein complexes Ib-IX and IIb-IIIa. J Clin Invest. 1990 Sep;86(3):785–792. doi: 10.1172/JCI114775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Marco L., Mazzuccato M., Grazia Del Ben M., Budde U., Federici A. B., Girolami A., Ruggeri Z. M. Type IIB von Willebrand factor with normal sialic acid content induces platelet aggregation in the absence of ristocetin. Role of platelet activation, fibrinogen, and two distinct membrane receptors. J Clin Invest. 1987 Aug;80(2):475–482. doi: 10.1172/JCI113095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Donnér M., Holmberg L., Nilsson I. M. Type IIB von Willebrand's disease with probable autosomal recessive inheritance and presenting as thrombocytopenia in infancy. Br J Haematol. 1987 Jul;66(3):349–354. doi: 10.1111/j.1365-2141.1987.tb06922.x. [DOI] [PubMed] [Google Scholar]
  9. Federici A. B., Bader R., Pagani S., Colibretti M. L., De Marco L., Mannucci P. M. Binding of von Willebrand factor to glycoproteins Ib and IIb/IIIa complex: affinity is related to multimeric size. Br J Haematol. 1989 Sep;73(1):93–99. doi: 10.1111/j.1365-2141.1989.tb00226.x. [DOI] [PubMed] [Google Scholar]
  10. Fujimura Y., Titani K., Holland L. Z., Roberts J. R., Kostel P., Ruggeri Z. M., Zimmerman T. S. A heparin-binding domain of human von Willebrand factor. Characterization and localization to a tryptic fragment extending from amino acid residue Val-449 to Lys-728. J Biol Chem. 1987 Feb 5;262(4):1734–1739. [PubMed] [Google Scholar]
  11. Fujimura Y., Titani K., Holland L. Z., Russell S. R., Roberts J. R., Elder J. H., Ruggeri Z. M., Zimmerman T. S. von Willebrand factor. A reduced and alkylated 52/48-kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib. J Biol Chem. 1986 Jan 5;261(1):381–385. [PubMed] [Google Scholar]
  12. Ginsburg D., Konkle B. A., Gill J. C., Montgomery R. R., Bockenstedt P. L., Johnson T. A., Yang A. Y. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci U S A. 1989 May;86(10):3723–3727. doi: 10.1073/pnas.86.10.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grainick H. R., Williams S. B., Coller B. S. Asialo von Willebrand factor interactions with platelets. Interdependence of glycoproteins Ib and IIb/IIIa for binding and aggregation. J Clin Invest. 1985 Jan;75(1):19–25. doi: 10.1172/JCI111673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grainick H. R., Williams S. B., McKeown L. P., Rick M. E., Maisonneuve P., Jenneau C., Sultan Y. Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor. J Clin Invest. 1985 Oct;76(4):1522–1529. doi: 10.1172/JCI112132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gralnick H. R., Williams S. B., Morisato D. K. Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets. Blood. 1981 Aug;58(2):387–397. [PubMed] [Google Scholar]
  16. Holmberg L., Nilsson I. M., Borge L., Gunnarsson M., Sjörin E. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand's disease. N Engl J Med. 1983 Oct 6;309(14):816–821. doi: 10.1056/NEJM198310063091402. [DOI] [PubMed] [Google Scholar]
  17. Konkle B. A., Ginsburg D. The addition of endothelial cell growth factor and heparin to human umbilical vein endothelial cell cultures decreases plasminogen activator inhibitor-1 expression. J Clin Invest. 1988 Aug;82(2):579–585. doi: 10.1172/JCI113635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Marti T., Rösselet S. J., Titani K., Walsh K. A. Identification of disulfide-bridged substructures within human von Willebrand factor. Biochemistry. 1987 Dec 15;26(25):8099–8109. doi: 10.1021/bi00399a013. [DOI] [PubMed] [Google Scholar]
  19. Miller J. L., Cunningham D., Lyle V. A., Finch C. N. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4761–4765. doi: 10.1073/pnas.88.11.4761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mohri H., Fujimura Y., Shima M., Yoshioka A., Houghten R. A., Ruggeri Z. M., Zimmerman T. S. Structure of the von Willebrand factor domain interacting with glycoprotein Ib. J Biol Chem. 1988 Dec 5;263(34):17901–17904. [PubMed] [Google Scholar]
  21. Mohri H., Yoshioka A., Zimmerman T. S., Ruggeri Z. M. Isolation of the von Willebrand factor domain interacting with platelet glycoprotein Ib, heparin, and collagen and characterization of its three distinct functional sites. J Biol Chem. 1989 Oct 15;264(29):17361–17367. [PubMed] [Google Scholar]
  22. Murray E. W., Giles A. R., Bridge P. J., Peake I. R., Lillicrap D. P. Cosegregation of von Willebrand factor gene polymorphisms and possible germinal mosaicism in type IIB von Willebrand disease. Blood. 1991 Apr 1;77(7):1476–1483. [PubMed] [Google Scholar]
  23. Pareti F. I., Fujimura Y., Dent J. A., Holland L. Z., Zimmerman T. S., Ruggeri Z. M. Isolation and characterization of a collagen binding domain in human von Willebrand factor. J Biol Chem. 1986 Nov 15;261(32):15310–15315. [PubMed] [Google Scholar]
  24. Raines G., Aumann H., Sykes S., Street A. Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel. Thromb Res. 1990 Nov 1;60(3):201–212. doi: 10.1016/0049-3848(90)90181-b. [DOI] [PubMed] [Google Scholar]
  25. Randi A. M., Rabinowitz I., Mancuso D. J., Mannucci P. M., Sadler J. E. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 Apr;87(4):1220–1226. doi: 10.1172/JCI115122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ribba A. S., Lavergne J. M., Bahnak B. R., Derlon A., Piétu G., Meyer D. Duplication of a methionine within the glycoprotein Ib binding domain of von Willebrand factor detected by denaturing gradient gel electrophoresis in a patient with type IIB von Willebrand disease. Blood. 1991 Oct 1;78(7):1738–1743. [PubMed] [Google Scholar]
  27. Roth G. J., Titani K., Hoyer L. W., Hickey M. J. Localization of binding sites within human von Willebrand factor for monomeric type III collagen. Biochemistry. 1986 Dec 30;25(26):8357–8361. doi: 10.1021/bi00374a004. [DOI] [PubMed] [Google Scholar]
  28. Ruggeri Z. M., Lombardi R., Gatti L., Bader R., Valsecchi C., Zimmerman T. S. Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von willebrand factor. Blood. 1982 Dec;60(6):1453–1456. [PubMed] [Google Scholar]
  29. Ruggeri Z. M., Pareti F. I., Mannucci P. M., Ciavarella N., Zimmerman T. S. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Engl J Med. 1980 May 8;302(19):1047–1051. doi: 10.1056/NEJM198005083021902. [DOI] [PubMed] [Google Scholar]
  30. Ruggeri Z. M. Structure and function of von Willebrand factor: relationship to von Willebrand's disease. Mayo Clin Proc. 1991 Aug;66(8):847–861. doi: 10.1016/s0025-6196(12)61204-x. [DOI] [PubMed] [Google Scholar]
  31. Ruggeri Z. M., Zimmerman T. S. Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest. 1980 Jun;65(6):1318–1325. doi: 10.1172/JCI109795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ruggeri Z. M., Zimmerman T. S. von Willebrand factor and von Willebrand disease. Blood. 1987 Oct;70(4):895–904. [PubMed] [Google Scholar]
  33. Schneppenheim R., Plendl H., Budde U. Luminography--an alternative assay for detection of von Willebrand factor multimers. Thromb Haemost. 1988 Oct 31;60(2):133–136. [PubMed] [Google Scholar]
  34. Titani K., Kumar S., Takio K., Ericsson L. H., Wade R. D., Ashida K., Walsh K. A., Chopek M. W., Sadler J. E., Fujikawa K. Amino acid sequence of human von Willebrand factor. Biochemistry. 1986 Jun 3;25(11):3171–3184. doi: 10.1021/bi00359a015. [DOI] [PubMed] [Google Scholar]
  35. Wagner D. D. Cell biology of von Willebrand factor. Annu Rev Cell Biol. 1990;6:217–246. doi: 10.1146/annurev.cb.06.110190.001245. [DOI] [PubMed] [Google Scholar]
  36. Ware J., Dent J. A., Azuma H., Sugimoto M., Kyrle P. A., Yoshioka A., Ruggeri Z. M. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2946–2950. doi: 10.1073/pnas.88.7.2946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. de Groot P. G., Federici A. B., de Boer H. C., d'Alessio P., Mannucci P. M., Sixma J. J. von Willebrand factor synthesized by endothelial cells from a patient with type IIB von Willebrand disease supports platelet adhesion normally but has an increased affinity for platelets. Proc Natl Acad Sci U S A. 1989 May;86(10):3793–3797. doi: 10.1073/pnas.86.10.3793. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES