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. 1991 Jun 1;88(11):4761–4765. doi: 10.1073/pnas.88.11.4761

Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease.

J L Miller 1, D Cunningham 1, V A Lyle 1, C N Finch 1
PMCID: PMC51746  PMID: 2052556

Abstract

Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor (vWF) by patient platelets. Although the platelet glycoprotein (GP) Ib/IX complex is known to constitute the platelet's ristocetin-dependent receptor for vWF, a unique structural abnormality within this complex has not previously been identified in PT-vWD. Using the polymerase chain reaction to amplify genomic DNA coding for the alpha chain of GP Ib (GP Ib alpha) and then sequencing the amplified DNA following cloning into M13mp18 and M13mp19 phage vectors, we have found a single point mutation in the GP Ib alpha coding region of PT-vWD DNA resulting in the substitution of valine for glycine at residue 233. This substitution within the vWF-binding region of GP Ib alpha is likely to exert a significant influence on the conformation of the resulting protein. Competitive oligonucleotide primer assay for this mutation showed a homozygous wild-type pattern in genomic DNA from the 161 normal volunteers studied and from 6 phenotypically normal members of a PT-vWD family. All 7 affected members of this family studied were heterozygous for the mutant allele. Platelet GP Ib alpha mRNA reverse-transcribed and studied by competitive oligonucleotide primer assay showed similar expression of the mutant and wild-type alleles in the affected PT-vWD patients. Absence in the normal population, tight linkage with phenotypic expression of disease, and absence of any additional abnormality of GP Ib alpha in these patients identify the glycine-to-valine substitution as a point mutation underlying functional abnormality of the vWF receptor in PT-vWD.

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Selected References

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

  1. Andrews R. K., Booth W. J., Gorman J. J., Castaldi P. A., Berndt M. C. Purification of botrocetin from Bothrops jararaca venom. Analysis of the botrocetin-mediated interaction between von Willebrand factor and the human platelet membrane glycoprotein Ib-IX complex. Biochemistry. 1989 Oct 17;28(21):8317–8326. doi: 10.1021/bi00447a009. [DOI] [PubMed] [Google Scholar]
  2. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berndt M. C., Du X. P., Booth W. J. Ristocetin-dependent reconstitution of binding of von Willebrand factor to purified human platelet membrane glycoprotein Ib-IX complex. Biochemistry. 1988 Jan 26;27(2):633–640. doi: 10.1021/bi00402a021. [DOI] [PubMed] [Google Scholar]
  4. Brower M. S., Levin R. I., Garry K. Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins. J Clin Invest. 1985 Feb;75(2):657–666. doi: 10.1172/JCI111744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bryckaert M. C., Pietu G., Ruan C., Tobelem G., Girma J. P., Meyer D., Larrieu M. J., Caen J. P. Abnormality of glycoprotein Ib in two cases of "pseudo"-von Willebrand's disease. J Lab Clin Med. 1985 Oct;106(4):393–400. [PubMed] [Google Scholar]
  6. Carothers A. M., Urlaub G., Mucha J., Grunberger D., Chasin L. A. Point mutation analysis in a mammalian gene: rapid preparation of total RNA, PCR amplification of cDNA, and Taq sequencing by a novel method. Biotechniques. 1989 May;7(5):494-6, 498-9. [PubMed] [Google Scholar]
  7. Du X., Beutler L., Ruan C., Castaldi P. A., Berndt M. C. Glycoprotein Ib and glycoprotein IX are fully complexed in the intact platelet membrane. Blood. 1987 May;69(5):1524–1527. [PubMed] [Google Scholar]
  8. Finch C. N., Miller J. L., Lyle V. A., Handin R. I. Evidence that an abnormality in the glycoprotein Ib alpha gene is not the cause of abnormal platelet function in a family with classic Bernard-Soulier disease. Blood. 1990 Jun 15;75(12):2357–2362. [PubMed] [Google Scholar]
  9. George J. N., Nurden A. T., Phillips D. R. Molecular defects in interactions of platelets with the vessel wall. N Engl J Med. 1984 Oct 25;311(17):1084–1098. doi: 10.1056/NEJM198410253111705. [DOI] [PubMed] [Google Scholar]
  10. Gibbs R. A., Nguyen P. N., Caskey C. T. Detection of single DNA base differences by competitive oligonucleotide priming. Nucleic Acids Res. 1989 Apr 11;17(7):2437–2448. doi: 10.1093/nar/17.7.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Handa M., Titani K., Holland L. Z., Roberts J. R., Ruggeri Z. M. The von Willebrand factor-binding domain of platelet membrane glycoprotein Ib. Characterization by monoclonal antibodies and partial amino acid sequence analysis of proteolytic fragments. J Biol Chem. 1986 Sep 25;261(27):12579–12585. [PubMed] [Google Scholar]
  12. Lange K., Weeks D., Boehnke M. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5(6):471–472. doi: 10.1002/gepi.1370050611. [DOI] [PubMed] [Google Scholar]
  13. Lopez J. A., Chung D. W., Fujikawa K., Hagen F. S., Papayannopoulou T., Roth G. J. Cloning of the alpha chain of human platelet glycoprotein Ib: a transmembrane protein with homology to leucine-rich alpha 2-glycoprotein. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5615–5619. doi: 10.1073/pnas.84.16.5615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
  15. Miller J. L., Castella A. Platelet-type von Willebrand's disease: characterization of a new bleeding disorder. Blood. 1982 Sep;60(3):790–794. [PubMed] [Google Scholar]
  16. Miller J. L., Hustad K. O., Kupinski J. M., Lyle V. A., Kunicki T. J. Increased platelet sensitivity to ristocetin is predicted by the binding characteristics of a GPIb/IX determinant. Br J Haematol. 1990 Mar;74(3):313–319. doi: 10.1111/j.1365-2141.1990.tb02589.x. [DOI] [PubMed] [Google Scholar]
  17. Miller J. L., Kupinski J. M., Castella A., Ruggeri Z. M. von Willebrand factor binds to platelets and induces aggregation in platelet-type but not type IIB von Willebrand disease. J Clin Invest. 1983 Nov;72(5):1532–1542. doi: 10.1172/JCI111112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miller J. L., Ruggeri Z. M., Lyle V. A. Unique interactions of asialo von Willebrand factor with platelets in platelet-type von Willebrand disease. Blood. 1987 Dec;70(6):1804–1809. [PubMed] [Google Scholar]
  19. Pincus M. R., Brandt-Rauf P. W. Protein structure and cancer. Cancer Invest. 1986;4(2):185–195. doi: 10.3109/07357908609038261. [DOI] [PubMed] [Google Scholar]
  20. Reddy E. P., Reynolds R. K., Santos E., Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982 Nov 11;300(5888):149–152. doi: 10.1038/300149a0. [DOI] [PubMed] [Google Scholar]
  21. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Seeburg P. H., Colby W. W., Capon D. J., Goeddel D. V., Levinson A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984 Nov 1;312(5989):71–75. doi: 10.1038/312071a0. [DOI] [PubMed] [Google Scholar]
  23. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  24. Takahashi H., Handa M., Watanabe K., Ando Y., Nagayama R., Hattori A., Shibata A., Federici A. B., Ruggeri Z. M., Zimmerman T. S. Further characterization of platelet-type von Willebrand's disease in Japan. Blood. 1984 Dec;64(6):1254–1262. [PubMed] [Google Scholar]
  25. Takahashi H. Studies on the pathophysiology and treatment of von Willebrand's disease. IV. Mechanism of increased ristocetin-induced platelet aggregation in von Willebrand's disease. Thromb Res. 1980 Sep 15;19(6):857–867. doi: 10.1016/0049-3848(80)90013-4. [DOI] [PubMed] [Google Scholar]
  26. Vicente V., Houghten R. A., Ruggeri Z. M. Identification of a site in the alpha chain of platelet glycoprotein Ib that participates in von Willebrand factor binding. J Biol Chem. 1990 Jan 5;265(1):274–280. [PubMed] [Google Scholar]
  27. Vicente V., Kostel P. J., Ruggeri Z. M. Isolation and functional characterization of the von Willebrand factor-binding domain located between residues His1-Arg293 of the alpha-chain of glycoprotein Ib. J Biol Chem. 1988 Dec 5;263(34):18473–18479. [PubMed] [Google Scholar]
  28. Weiss H. J., Meyer D., Rabinowitz R., Pietu G., Girma J. P., Vicic W. J., Rogers J. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med. 1982 Feb 11;306(6):326–333. doi: 10.1056/NEJM198202113060603. [DOI] [PubMed] [Google Scholar]
  29. Wenger R. H., Kieffer N., Wicki A. N., Clemetson K. J. Structure of the human blood platelet membrane glycoprotein Ib alpha gene. Biochem Biophys Res Commun. 1988 Oct 14;156(1):389–395. doi: 10.1016/s0006-291x(88)80853-2. [DOI] [PubMed] [Google Scholar]
  30. Wicki A. N., Clemetson K. J. Structure and function of platelet membrane glycoproteins Ib and V. Effects of leukocyte elastase and other proteases on platelets response to von Willebrand factor and thrombin. Eur J Biochem. 1985 Nov 15;153(1):1–11. doi: 10.1111/j.1432-1033.1985.tb09259.x. [DOI] [PubMed] [Google Scholar]
  31. Wicki A. N., Walz A., Gerber-Huber S. N., Wenger R. H., Vornhagen R., Clemetson K. J. Isolation and characterization of human blood platelet mRNA and construction of a cDNA library in lambda gt11. Confirmation of the platelet derivation by identification of GPIb coding mRNA and cloning of a GPIb coding cDNA insert. Thromb Haemost. 1989 Jun 30;61(3):448–453. [PubMed] [Google Scholar]

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