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. 1989 May;86(10):3723–3727. doi: 10.1073/pnas.86.10.3723

Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.

D Ginsburg 1, B A Konkle 1, J C Gill 1, R R Montgomery 1, P L Bockenstedt 1, T A Johnson 1, A Y Yang 1
PMCID: PMC287212  PMID: 2786201

Abstract

von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF). Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients. By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets. A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing. In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain. Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma.

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Selected References

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

  1. Bahou W. F., Bowie E. J., Fass D. N., Ginsburg D. Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus. Blood. 1988 Jul;72(1):308–313. [PubMed] [Google Scholar]
  2. Batlle J., Lopez Fernandez M. F., Campos M., Justica B., Berges C., Navarro J. L., Diaz Cremades J. M., Kasper C. K., Dent J. A., Ruggeri Z. M. The heterogeneity of type IIA von Willebrand's disease: studies with protease inhibitors. Blood. 1986 Dec;68(6):1207–1212. [PubMed] [Google Scholar]
  3. Berkowitz S. D., Dent J., Roberts J., Fujimura Y., Plow E. F., Titani K., Ruggeri Z. M., Zimmerman T. S. Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. J Clin Invest. 1987 Feb;79(2):524–531. doi: 10.1172/JCI112843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonthron D. T., Handin R. I., Kaufman R. J., Wasley L. C., Orr E. C., Mitsock L. M., Ewenstein B., Loscalzo J., Ginsburg D., Orkin S. H. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature. 1986 Nov 20;324(6094):270–273. doi: 10.1038/324270a0. [DOI] [PubMed] [Google Scholar]
  5. Bonthron D., Orr E. C., Mitsock L. M., Ginsburg D., Handin R. I., Orkin S. H. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res. 1986 Sep 11;14(17):7125–7127. doi: 10.1093/nar/14.17.7125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collins C. J., Underdahl J. P., Levene R. B., Ravera C. P., Morin M. J., Dombalagian M. J., Ricca G., Livingston D. M., Lynch D. C. Molecular cloning of the human gene for von Willebrand factor and identification of the transcription initiation site. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4393–4397. doi: 10.1073/pnas.84.13.4393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ginsburg D., Handin R. I., Bonthron D. T., Donlon T. A., Bruns G. A., Latt S. A., Orkin S. H. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science. 1985 Jun 21;228(4706):1401–1406. doi: 10.1126/science.3874428. [DOI] [PubMed] [Google Scholar]
  9. Girma J. P., Meyer D., Verweij C. L., Pannekoek H., Sixma J. J. Structure-function relationship of human von Willebrand factor. Blood. 1987 Sep;70(3):605–611. [PubMed] [Google Scholar]
  10. Gralnick H. R., Williams S. B., McKeown L. P., Maisonneuve P., Jenneau C., Sultan Y., Rick M. E. In vitro correction of the abnormal multimeric structure of von Willebrand factor in type IIa von Willebrand's disease. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5968–5972. doi: 10.1073/pnas.82.17.5968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kieffer N., Guichard J., Farcet J. P., Vainchenker W., Breton-Gorius J. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem. 1987 Apr 1;164(1):189–195. doi: 10.1111/j.1432-1033.1987.tb11010.x. [DOI] [PubMed] [Google Scholar]
  12. Kunicki T. J., Montgomery R. R., Schullek J. Cleavage of human von Willebrand factor by platelet calcium-activated protease. Blood. 1985 Feb;65(2):352–356. [PubMed] [Google Scholar]
  13. Levene R. B., Booyse F. M., Chediak J., Zimmerman T. S., Livingston D. M., Lynch D. C. Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6550–6554. doi: 10.1073/pnas.84.18.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mohrenweiser H. W., Wurzinger K. H., Neel J. V. Frequency and distribution of rare electrophoretic mobility variants in a population of human newborns in Ann Arbor, Michigan. Ann Hum Genet. 1987 Oct;51(Pt 4):303–316. doi: 10.1111/j.1469-1809.1987.tb01065.x. [DOI] [PubMed] [Google Scholar]
  15. Newman P. J., Gorski J., White G. C., 2nd, Gidwitz S., Cretney C. J., Aster R. H. Enzymatic amplification of platelet-specific messenger RNA using the polymerase chain reaction. J Clin Invest. 1988 Aug;82(2):739–743. doi: 10.1172/JCI113656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ngo K. Y., Glotz V. T., Koziol J. A., Lynch D. C., Gitschier J., Ranieri P., Ciavarella N., Ruggeri Z. M., Zimmerman T. S. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2753–2757. doi: 10.1073/pnas.85.8.2753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rodeghiero F., Castaman G., Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood. 1987 Feb;69(2):454–459. [PubMed] [Google Scholar]
  18. Ruggeri Z. M., Zimmerman T. S. von Willebrand factor and von Willebrand disease. Blood. 1987 Oct;70(4):895–904. [PubMed] [Google Scholar]
  19. Sadler J. E., Shelton-Inloes B. B., Sorace J. M., Titani K. Cloning of cDNA and genomic DNA for human von Willebrand factor. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):515–523. doi: 10.1101/sqb.1986.051.01.063. [DOI] [PubMed] [Google Scholar]
  20. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  21. Shelton-Inloes B. B., Broze G. J., Jr, Miletich J. P., Sadler J. E. Evolution of human von Willebrand factor: cDNA sequence polymorphisms, repeated domains, and relationship to von Willebrand antigen II. Biochem Biophys Res Commun. 1987 Apr 29;144(2):657–665. doi: 10.1016/s0006-291x(87)80016-5. [DOI] [PubMed] [Google Scholar]
  22. Shelton-Inloes B. B., Chehab F. F., Mannucci P. M., Federici A. B., Sadler J. E. Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J Clin Invest. 1987 May;79(5):1459–1465. doi: 10.1172/JCI112974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Verweij C. L., Diergaarde P. J., Hart M., Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J. 1986 Aug;5(8):1839–1847. doi: 10.1002/j.1460-2075.1986.tb04435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Verweij C. L., Quadt R., Briët E., Dubbeldam K., van Ommen G. B., Pannekoek H. Genetic linkage of two intragenic restriction fragment length polymorphisms with von Willebrand's disease type IIA. Evidence for a defect in the von Willebrand factor gene. J Clin Invest. 1988 Apr;81(4):1116–1121. doi: 10.1172/JCI113425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wise R. J., Pittman D. D., Handin R. I., Kaufman R. J., Orkin S. H. The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell. 1988 Jan 29;52(2):229–236. doi: 10.1016/0092-8674(88)90511-9. [DOI] [PubMed] [Google Scholar]

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