Download PDF
Thromb Haemost 2002; 88(03): 421-426
DOI: 10.1055/s-0037-1613232
Review Article
Schattauer GmbH

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)

Stefan Lethagen
1   Departments of Coagulation Disorders, Malmö
,
Christina Isaksson
2   Paediatrics, Lund, University of Lund, Sweden
,
Charlotta Schaedel
2   Paediatrics, Lund, University of Lund, Sweden
,
Lars Holmberg
2   Paediatrics, Lund, University of Lund, Sweden
› Author Affiliations
Further Information

Publication History

Received 24 October 2001

Accepted after resubmission 31 May 2002

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Hereditary defects of the von Willebrand factor (VWF) gene cause von Willebrand’s disease (VWD) which shows great variability dependent on the nature and location of the mutation. We here describe the characteristics of a substitution of methionine for threonine 1156 in the D3 domain of the VWF, i.e. the domain involved in the intracellular multimerization of pro-VWF dimers. A VWD patient with severe symptoms was a compound heterozygote for the T1156M mutation and a null allele (Q2470X) on the other chromosome. This led to marked reduction of plasma VWF concentration to about 0.05 U/ml and an abnormality of VWF multimers as in type 2A VWD. Expression in vitro of the mutation demonstrated that 1156M-VWF is secreted from COS-7 cells in a much reduced amount and lacking large multimers. When coexpressed with normal VWF 1156M-VWF decreased the secretion of normal VWF in a dose-dependent manner, the secreted VWF showing all the multimers. Two relatives of the propositus were single heterozygotes for the T1156M mutation and were either asymptomatic or had the manifestations of mild type 1 VWD. The expression data and studies of platelet VWF indicate that the T1156M mutation results in intracellular retention of VWF rather than impaired synthesis. Three other members of the family were heterozygotes for the Q2470X mutation and demonstrated the variable expressivity of a null allele.

Keywords

Von Willebrand’s disease - mutation - COS-7 cell transfection
 

  • References

  • 1 Shelton-Inloes BB, Titani K, Sadler JE. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25: 3164-71.
    CrossrefPubMedGoogle Scholar
  • 2 Marti T, Rösseler SJ, Titani K, Walsh KA. Identification of disulfidebridged substructures within human von Willebrand factor. Biochemistry 1987; 26: 8099-109.
    CrossrefPubMedGoogle Scholar
  • 3 Voorberg J, Fontijn R, Calafat J, Janssen H, van Mourik JA, Pannekoek H. Assembly and routing of von Willebrand factor variants: the requirements for disulfide-linked dimerization reside within the carboxy-terminal 151 amino acids. J Cell Biol 1991; 113: 195-205.
    CrossrefPubMedGoogle Scholar
  • 4 Katsumi A, Tuley EA, Bodó I, Sadler JE. Localization of disulfide bonds in the cystine knot domain of human von Willebrand factor. J Biol Chem 2000; 275: 25585-94.
    CrossrefPubMedGoogle Scholar
  • 5 Verweij CL, Hart M, Pannekoek P. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. EMBO J 1987; 06: 2885-90.
    PubMedGoogle Scholar
  • 6 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Lyons SE, Bruck ME, Bowie EJW, Ginsburg D. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424-30.
    PubMedGoogle Scholar
  • 8 Gaucher G, Diéval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84: 1024-30.
    PubMedGoogle Scholar
  • 9 Schneppenheim R, Brassard J, Krey S, Budde U, Kunicki TJ, Holmberg L, Ware J, Ruggeri ZM. Defective dimerization of von Willebrand factor subunits due to a Cys -> Arg mutation in type IID von Willebrand disease. Proc Natl Acad Sci USA 1996; 93: 3581-6.
    CrossrefPubMedGoogle Scholar
  • 10 Schneppenheim R, Budde U, Obser T, Brassard J, Mainusch K, Ruggeri ZM, Schneppenheim S, Schwaab R, Oldenburg J. Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease. Blood 2001; 97: 2059-66.
    CrossrefPubMedGoogle Scholar
  • 11 Jorieux S, Gaucher C, Goudemand J, Mazurier C. A novel mutation in the D3 domain of von Willebrand factor markedly decreases its ability to bind factor VIII and affects its multimerization. Blood 1998; 92: 4663-70.
    PubMedGoogle Scholar
  • 12 Allen S, Abuzenadah AM, Blagg JL, Hinks J, Nesbitt IM, Goodeve AC, Gursel T, Ingerslev J, Peake IR, Daly ME. Two novel type 2N von Willebrand disease-causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor. Blood 2000; 95: 2000-7.
    PubMedGoogle Scholar
  • 13 Jorieux S, Fressinaud E, Goudemand J, Gaucher C, Meyer D, Mazurier C. Conformational changes in the D’ domain of von Willebrand factor induced by Cys25 and Cys95 mutations lead to factor VIII binding defect and multimeric impairment. Blood 2000; 95: 3139-45.
    PubMedGoogle Scholar
  • 14 Holmberg L, Nilsson IM, 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; 309: 816-21.
    CrossrefPubMedGoogle Scholar
  • 15 Mannucci PM, Lombardi R, Bader R, Vianello L, Federici AB, Solinas S, Mazzocconi MG, Mariani G. Heterogeneity of type 1 von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66: 796-802.
    PubMedGoogle Scholar
  • 16 Holmberg L, Karpman D, Isaksson C, Kristoffersson AC, Lethagen S, Schneppenheim R. Ins405AsnPro mutation in the von Willebrand factor propeptide in recessive type 2A (IIC) von Willebrand’s disease. Thromb Haemost 1998; 79: 718-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mancuso DJ, Tuley ED, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253-69.
    CrossrefPubMedGoogle Scholar
  • 18 Matsushita T, Sadler JE. Identification of amino acid residues essential for von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1995; 270: 13406-14.
    CrossrefPubMedGoogle Scholar
  • 19 Englender T, Lattuada A, Mannucci PM, Sadler JE, Inbal A. Analysis of Arg834Gln and Val902Glu type 2A von Willebrand disease mutations. Studies with recombinant von Willebrand factor and correlation with patient characteristics. Blood 1996; 87: 2788-94.
    CrossrefPubMedGoogle Scholar
  • 20 Eikenboom JCJ, Matsushita T, Reitsma PH, Tuley EA, Castaman G, Briet E, Sadler JE. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88: 2433-41.
    PubMedGoogle Scholar
  • 21 Castaman G, Eikenboom JCJ, Missiaglia E, Rodeghiero F. Autosomal dominant type 1 von Willebrand disease due to G3693T mutation (C1130F) in exon 26 of von Willebrand factor gene: description of five Italian families and evidence for a founder effect. Br J Haematol 2000; 108: 876-9.
    CrossrefPubMedGoogle Scholar
  • 22 Voorberg J, Fontijn R, van Mourik JA, Pannekoek H. Domains involved in multimer assembly of von Willebrand factor (vWF): multimerization is independent of dimerization. EMBO J 1990; 09: 797-803.
    PubMedGoogle Scholar
  • 23 Azuma H, Hayashi T, Dent JA, Ruggeri ZM, Ware J. Disulfide bond requirements for assembly of the platelet glycoprotein Ib-binding domain of von Willebrand factor. J Biol Chem 1993; 268: 2821-7.
    PubMedGoogle Scholar
  • 24 Dong Z, Thoma RS, Crimmins DL, McCourt DW, Tuley EA, Sadler JE. Disulfide bonds required to assemble functional von Willebrand factor multimers. J Biol Chem 1994; 269: 6753-8.
    PubMedGoogle Scholar
  • 25 Sadler JE. Biochemistry and genetics of von Willebrand factor. Ann Rev Biochem 1998; 67: 395-424.
    CrossrefPubMedGoogle Scholar
  • 26 Bodó I, Katsumi A, Tuley EA, Eikenboom JCJ, Dong Z, Sadler JE. Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood 2001; 98: 2973-9.
    CrossrefPubMedGoogle Scholar
  • 27 Casaña P, Martinez F, Haya S, Espinós C, Aznar JA. Association of the 3467C →T mutation (T1156M) in the von Willebrand’s gene with dominant type 1 von Willebrand’s disease. Ann Haematol 2001; 80: 381-3.
    CrossrefPubMedGoogle Scholar
  • 28 Lethagen S, Frick K, Isaksson C, Kristoffersson AC, Holmberg L. Revised classification and treatment of von Willebrand disease. Thromb Haemost 1998; 80: 199-200.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Nitu-Whalley IC, Riddell A, Lee CA, Pasi KJ, Owens D, Enayat MS, Perkins SJ, Jenkins PV. Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling. Thromb Haemost 2000; 84: 998-1004.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D, Meyer D, Peake IR, Rodeghiero F, Srivastava A. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-74.
    Article in Thieme ConnectPubMedGoogle Scholar