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Thromb Haemost 2008; 100(02): 211-216
DOI: 10.1160/TH08-03-0187
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease

Elsa Lanke
1   Department for Coagulation Disorders, University Hospital, Malmö, Sweden
,
Ann-Charlotte Kristoffersson
2   Department of Pediatrics, Lund University, Sweden
,
Malou Philips
3   Department of Clinical Biochemistry, Copenhagen University Hospital (Rigshospitalet), Denmark
,
Lars Holmberg
2   Department of Pediatrics, Lund University, Sweden
,
Stefan Lethagen
1   Department for Coagulation Disorders, University Hospital, Malmö, Sweden
4   Center for Haemostasis and Thrombosis, Copenhagen University Hospital (Rigshospitalet), Denmark
› Author AffiliationsFinancial support: The study was supported by grants from Baxter, Copenhagen University Hospital, Crafoord Foundation, CSL Behring, Malmö University Hospital, Medical Faculty at Lund University, Region Skåne, and Slättens Ideella Barnhjälp.
Further Information

Publication History

Received 25 March 2008

Accepted after minor revision 11 June 2008

Publication Date:
22 November 2017 (online)

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Summary

vonWillebrand factor (VWF) is a plasma protein that consists of a series of multimers of which the high-molecular-weight VWF multimers are the most potent in platelet adhesion and aggre-gation. The propeptide of theVWF (VWFpp) is known to be essential in the process of multimer assembly. Genetic studies were performed in a patient with a phenotype of vonWillebrand disease (VWD) characterized by very low plasma factorVIII and VWF levels and a VWF consisting of only a dimeric band and total absence of all multimers in plasma. The patient was found to be homozygous for the novel C570S mutation, caused by a 1709G>C transition in exon 14 of theVWF gene coding for the propeptide. Three asymptomatic relatives were found to be heterozygous. In-vitro mutagenesis and expression in COS-7 cells confirmed the detrimental effect of the mutation on VWF multimerization. Our findings show that the C570S mutation in the VWFpp abolishes multimerization of VWF. The mutation probably disrupts the normal configuration of the VWFpp, which is essential for correct orientation of the protomers and ultimately multimerization. The mutant amino acid is located in a region that is highly conserved across several species which underlines its critical role. This variant constitutes a distinct subtype of recessive 2AVWD with the exclusive presence of the dimeric form of VWF in plasma.

Keywords

Coagulation - COS-7 cell transfection - multimerization - propep-tide - von Willebrand disease
 

  • References

  • 1 Sadler JE, Budde U, Eikenboom JCJ. et al. Update on the pathophysiology and classification of von Wille-brand disease: a report of the Subcommittee on von Willebrand disease. J Thromb Haemost 2006; 04: 2103-2114.
    CrossrefPubMedGoogle Scholar
  • 2 Verweij CL, de Vries CJM, Distel B. et al. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res 1985; 13: 4699-4717.
    CrossrefPubMedGoogle Scholar
  • 3 Mancuso DJ, Tuley EA, Westfield LA. et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527.
    PubMedGoogle Scholar
  • 4 Fischer BE, Thomas KB, Schlokat U. et al. Triplet structure of human von Willebrand factor. Biochem J 1998; 331: 483-488.
    CrossrefPubMedGoogle Scholar
  • 5 Wagner DD, Olmsted JB, Marder VJ. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. J Cell Biol 1982; 95: 355-360.
    CrossrefPubMedGoogle Scholar
  • 6 Rosenberg JB, Foster PA, Kaufman RJ. Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J Clin Invest 1998; 101: 613-624.
    CrossrefPubMedGoogle Scholar
  • 7 Vischer UM, Wagner DD. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel-Palade bodies. Blood 1994; 83: 3536-3544.
    PubMedGoogle Scholar
  • 8 Sadler JE. von Willebrand factor: two sides of a coin. J Thromb Haemost 2005; 03: 1702-1709.
    CrossrefPubMedGoogle Scholar
  • 9 Purvis AR, Sadler JE. A covalent oxidoreductase intermediate in propeptide-dependent von Willebrand factor multimerization. J Biol Chem 2004; 279: 49982-49988.
    CrossrefPubMedGoogle Scholar
  • 10 Wagner DD. Cell biology of von Willebrand factor (review). Annu Rev Cell Biol 1990; 06: 217-246.
    CrossrefPubMedGoogle Scholar
  • 11 Voorberg J, Fontijn R, van Mourik JA. et al. Domains involved in multimer assembly of von Wille-brand (vWF):multimerization is independent ofdimer-ization. EMBO 1990; 09: 797-803.
    CrossrefPubMedGoogle Scholar
  • 12 Haberichter SL, Jozwiak MA, Rosenberg JB. et al. The von Willebrand factor propeptide (VWFpp) traffics an unrelated protein to storage. Arterioscler Thromb Vasc Biol 2002; 22: 921-926.
    CrossrefPubMedGoogle Scholar
  • 13 Fujikawa K, Suzuki H, McMullen B. et al. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 2001; 98: 1662-1666.
    CrossrefPubMedGoogle Scholar
  • 14 Zheng X, Chung D, Takayama TK. et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-41063.
    CrossrefPubMedGoogle Scholar
  • 15 Soejima K, Mimura N, Hirashima M. et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease?. J Biochem 2001; 130: 475-480.
    CrossrefPubMedGoogle Scholar
  • 16 Verweij CL, Hart M, Pannekoek H. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. EMBO 1987; 06: 2885-2890.
    CrossrefPubMedGoogle Scholar
  • 17 Wise RJ, Pittman DD, Handin RI. et al. The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell 1988; 52: 229-236.
    CrossrefPubMedGoogle Scholar
  • 18 Wagner DD, Saffaripour S, Bonfanti R. et al. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell 1991; 64: 403-413.
    CrossrefPubMedGoogle Scholar
  • 19 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Nat Acad Sci USA 1992; 89: 3531-3535.
    CrossrefPubMedGoogle Scholar
  • 20 Haberichter SL, Jacobi P, Montgomery RR. Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage. Blood 2003; 101: 1384-1391.
    CrossrefPubMedGoogle Scholar
  • 21 Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood 2000; 96: 1808-1815.
    PubMedGoogle Scholar
  • 22 Journet AM, Saffaripour S, Cramer EM. et al. von Willebrand factor storage requires intact prosequence cleavage site. Eur J Cell Biol 1993; 60: 31-41.
    PubMedGoogle Scholar
  • 23 Bahnak BR, Lavergne JM, Rotschild C. et al. A stop cod on in a patient with severe type III von Willebrand disease. Blood 1991; 78: 1148-1149.
    PubMedGoogle Scholar
  • 24 Gaucher C, Diéval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84: 1024-1030.
    PubMedGoogle Scholar
  • 25 Zhang ZP, Blombäck M, Egberg N. et al. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics 1994; 21: 188-193.
    CrossrefPubMedGoogle Scholar
  • 26 Schneppenheim R, Krey S, Bergmann F. et al. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet 1994; 94: 640-652.
    PubMedGoogle Scholar
  • 27 Schneppenheim R, Thomas KB, Krey S. et al. Identification of a candidate missense mutation in a family with von Willebrand disease type IIC. Hum Genet 1995; 95: 681-686.
    PubMedGoogle Scholar
  • 28 Gaucher C, Mazurier C. Phenotype IIC von Willebrand disease: the expression of three mutant recombinant von Willebrand factors (VWF) confirms the importance of the D2 domain of VWF propeptide in the multimer assembly process (abstract). Br J Haemat 1996; 93 (Suppl. 02) 15 Abstract 58.
    CrossrefPubMedGoogle Scholar
  • 29 Eikenboom JCJ, Castaman G, Vos HL. et al. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79: 709-717.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Gaucher C, Uno H, Yamazaki T. et al. A new candidate mutation (N528S) within the von Willebrand factor propeptide identified in a Japanese patient with phenotype IIC of von Willebrand disease. Eur J Haematol 1998; 61: 145-148.
    PubMedGoogle Scholar
  • 31 Holmberg L, Karpman D, Isaksson C. et al. Ins405AsnPro mutation in the von Willebrand factor propeptide in recessive type 2A (IIC) von Willebrand's disease. Thromb Haemost 1998; 79: 718-722.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Allen S, Abuzenadah AM, Hinks J. et al. A novel vonWillebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion. Blood 2000; 96: 560-568.
    PubMedGoogle Scholar
  • 33 Baronciani L, Cozzi G, Canciani MT. et al. Molecular characterization of a multiethnic group of 21 patients with type 3 von Willebrand disease. Thromb Haemost 2000; 84: 536-540.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Rosenberg JB, Haberichter SL, Jozwiak MA. et al. The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF. Blood 2002; 100: 1699-1706.
    CrossrefPubMedGoogle Scholar
  • 35 Baronciani L, Cozzi G, Canciani MT. et al. Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients. Blood Cells Mol Dis 2003; 30: 264-270.
    CrossrefPubMedGoogle Scholar
  • 36 Casonato A, Sartorello F, Cattini MG. et al. An Arg760Cys mutation in the consensus sequence of the von Willebrand factor propeptide cleavage site is responsible for a new von Willebrand disease variant. Blood 2003; 101: 151-156.
    CrossrefPubMedGoogle Scholar
  • 37 Ruggeri ZM, Nilsson IM, Lombardi R. et al. Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand's disease (Type IIC). J Clin Invest 1982; 70: 1124-1127.
    CrossrefPubMedGoogle Scholar
  • 38 Strandberg K, Lethagen S, Andersson K. et al. Evaluation of a rapid automated assay for analysis of von Willebrand ristocetin cofactor activity. Clin Appl Thromb Hemost 2006; 12: 61-67.
    CrossrefPubMedGoogle Scholar
  • 39 Knudsen TT, Thorsen S, Jensen SA. et al. Effect of intravenous N-acetylcysteine infusion on haemostatic parameters in healthy subjects. Gut 2005; 54: 515-521.
    CrossrefPubMedGoogle Scholar
  • 40 Lethagen S, Isaksson C, Schaedel C. et al. Von Willebrand's disease caused by compound heterozygosity for a substitution mutation (T1156M) in the D3 domain of the von Willebrand factor and a stop mutation (Q2470X). Thromb Haemost 2002; 88: 421-426.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Englender T, Lattuada A, Mannucci PM. et al. Analysis of Arg834G ln and Va l902Glutype 2A von Willebrand disease mutations. Studies with recombinant von Willebrand factor and correlation with patient characteristics. Blood 1996; 87: 2788-2794.
    CrossrefPubMedGoogle Scholar
  • 42 Bahnak BR, Lavergne JM, Ferreira V. et al. Comparison of the primary structure of the functional domains of human and porcine von Willebrand factor that mediate platelet adhesion. Biochem Biophys Res Com 1992; 182: 561-568.
    CrossrefPubMedGoogle Scholar
  • 43 Lavergne JM, Piao YC, Ferreira V. et al. Primary structure of the factor VIII binding domain of human, porcine and rabbit von Willebrand factor. Biochem Biophys Res Com 1993; 194: 1019-1024.
    CrossrefPubMedGoogle Scholar
  • 44 Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, positions-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994; 22: 4673-4680.
    CrossrefPubMedGoogle Scholar
  • 45 Available at http://www.expasy.org Last accessed November 2006.
    PubMed
  • 46 Baronciani L, Federici AB, Cozzi G. et al. Biochemical characterization of a recombinant von Willebrand factor (VWF) with combined type 2B and type 1 defects in the VWF gene in two patients with a type 2A phenotype of von Willebrand disease. J Thromb Haemost 2007; 05: 282-288.
    CrossrefPubMedGoogle Scholar
  • 47 Journet AM, Saffaripour S, Wagner DD. Requirement for both D domains of the propolypeptide in von Willebrand factor multimerization and storage. Thromb Haemost 1993; 70: 1053-1057.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Haberichter SL, Merricks EP, Fahs SA. et al. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 2005; 105: 145-152.
    CrossrefPubMedGoogle Scholar
  • 49 Hommais A, Stepanian A, Fressinaud E. et al. Impaired dimerization of von Willebrand factor subunit due to mutation A280ID in the CK domain results in a recessive type 2A subtype IID von Willebrand disease. Thromb Haemost 2006; 95: 776-781.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Tjernberg P, Vos HL, Spaargaren-van Riel CC. et al. Differential effects of the loss of intrachain- versus in-terchain-disulfide bonds in the cysteine-knot domain of von Willebrand factor on the clinical phenotype of von Willebrand disease. Thromb Haemost 2006; 96: 717-724.
    Article in Thieme ConnectPubMedGoogle Scholar