Impaired dimerization of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease

Antoine Hommais; Alain Stépanian; Edith Fressinaud; Claudine Mazurier; Katia Pouymayou; Dominique Meyer; Jean-Pierre Girma; Anne-Sophie Ribba

doi:10.1160/TH06-01-0026

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(05): 776-781
DOI: 10.1160/TH06-01-0026

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Impaired dimerization of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease

Antoine Hommais

¹INSERM U. 770, Hôpital de Bicêtre, Université Paris-Sud 11, Faculté de Médecine Paris-Sud, Paris

,

Alain Stépanian

¹INSERM U. 770, Hôpital de Bicêtre, Université Paris-Sud 11, Faculté de Médecine Paris-Sud, Paris

,

Edith Fressinaud

²Laboratoire d’Hématologie, CHU Nantes

,

Claudine Mazurier

³Laboratoire Français du Fractionnement et des Biotechnologies, Lille

,

Katia Pouymayou

⁴INSERM UMR 626, C.H.U. Timone, Marseille; France

,

Dominique Meyer

¹INSERM U. 770, Hôpital de Bicêtre, Université Paris-Sud 11, Faculté de Médecine Paris-Sud, Paris

,

Jean-Pierre Girma

¹INSERM U. 770, Hôpital de Bicêtre, Université Paris-Sud 11, Faculté de Médecine Paris-Sud, Paris

,

Anne-Sophie Ribba

¹INSERM U. 770, Hôpital de Bicêtre, Université Paris-Sud 11, Faculté de Médecine Paris-Sud, Paris

› Author Affiliations

Abstract

Summary

The CK domain of von Willebrand factor (VWF) is involved in the dimerization of the protein.We identified the homozygous substitution A2801D of the CK domain in two siblings. Patients had low levels of VWF in plasma, abnormal ristocetin-induced binding to platelets and abnormal multimeric pattern witha lack of high molecular weight (HMW) forms and the presence of intervening bands between normal multimers. Accordingly, they were classified in type 2A, subtype IID, von Willebrand disease (VWD). Both asymptomatic parents carried the mutation at the heterozygous state.Their plasmaVWF exhibited the full range of multimers found in normal plasma.When analyzed by high resolution gel electrophoresis, very faint bands corresponding to the position of intervening bands of the propositus can be observed. The mutated recombinant (r)VWF-D2801, the hybrid rVWF-A/D2801 and the mutated C-terminal VWF fragment rSPII-D2801 were expressed in COS-7 cells. rVWF-D2801 showed an abnormal multimeric distribution similar to that of the propositus’VWF with intervening bands and a lack of HMW species. rVWF-A/D2801 exhibited the full range of multimers and the aberrant sized forms observed both in propositus’VWF and in rVWF-D2801. rSPII-WT assembled correctly into a dimer of 220 kDa. rSPII-D2801 appeared as a mixture of monomeric and dimeric forms which may be related to the abnormal multimeric pattern of the propositus and both mutated rVWF. We concluded that mutation A2801D disturbs the folding of the CK domain, which may result in a mixture of monomers and dimers of VWF. Multimers containing either an odd or even number of mature subunits are produced, and the presence of monomers appears to limit the degree of multimerization. In the heterozygousVWF,the presence of normal dimers improves the multimerization process. In conclusion, the mutation A2801D appears to be responsible fora recessive type 2A, subtype IID, VWD.

Keywords

von Willebrand factor - von Willebrand disease - type 2A VWF - dimerization - CK domain

Full Text

References

References
1 Ruggeri ZM. Von Willebrand factor. Curr Opin Hematol 2003; 10: 142-9.
2 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annual Review of Biochemistry 1998; 67: 395-424.
3 Wagner DD, Lawrence SO, Ohlsson-Wihelm BM. et al. Topology and order of formation of interchain disulfide bonds in von Willebrand Factor. Blood 1987; 69: 27-32.
4 Voorberg J, Fontijn R, Calafat J. et al. 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.
5 Katsumi A, Tuley EA, Bodo I. et al. Localization of disulfide bonds in the cystine knot domain of human von Willebrand factor. J Biol Chem 2000; 275: 25585-94.
6 Voorberg J, Fontijn R, van Mourik JA. et al. Domains involved in multimer assembly of von Willebrand factor (vwf) - multimerization is independent of dimerization. Embo J 1990; 09: 797-803.
7 Mayadas TN, Wagner DD. von Willebrand factor biosynthesis and processing. Ann NY Acad Sci 1991; 614: 153-66.
8 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: 1699-706.
9 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
10 Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update. Semin Hematol 2005; 42: 15-28.
11 Ribba AS, Voorberg J, Meyer D. et al. Characterization of Recombinant von Willebrand Factor Corresponding to Mutations in Type-IIA and Type-IIB von Willebrand Disease. J Biol Chem 1992; 267: 23209-15.
12 Lankhof H, Damas C, Schiphorst ME. et al. Recombinant vWF type 2A mutants R834Q and R834W show a defect in mediating platelet adhesion to collagen, independent of enhanced sensitivity to a plasma protease. Thromb Haemost 1999; 81: 976-83.
13 Tsai HM, Sussman II, Ginsburg D. et al. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: Inhibition by doxycycline and by monoclonal antibody VP-1. Blood 1997; 89: 1954-62.
14 Hassenpflug WA, Budde U, Obser T. et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006; Mar 15; 107: 2339-45.
15 Meyer D, Fressinaud E, Hilbert L. et al. Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function. Best Pract Res Clin Haematol 2001; 14: 349-64.
16 Schneppenheim R, Brassard J, Krey S. et al. 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.
17 Enayat MS, Guilliatt AM, Surdhar GK. et al. Aberrant dimerization of von Willebrand factor as the result of mutations in the carboxy-terminal region: identification of3 mutations in members of 3 different families with type 2A (Phenotype IID) von Willebrand disease. Blood 2001; 98: 674-80.
18 Tjernberg P, Vos HL, Castaman G. et al. Dimerization and multimerization defects of von Willebrand factor due to mutated cysteine residues. J Thromb Haemost 2004; 02: 257-65.
19 Schneppenheim R, Budde U, Obser T. et al. Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease. Blood 2001; 97: 2059-66.
20 Veyradier A, Fressinaud E, Meyer D. Laboratory diagnosis of von Willebrand disease. InternJ Clin Lab Res 1998; 28: 201-10.
21 Obert B, Tout H, Veyradier A. et al. Estimation of the von Willebrand factor-cleaving protease in plasma using monoclonal antibodies to vWF. Thromb Haemost 1999; 82: 1382-5.
22 Siguret V, Ribba AS, Christophe O. et al. Characterization of recombinant von Willebrand factors mutated on cysteine 509 or 695. Thromb Haemost 1996; 76: 453-9.
23 Hilbert L, Gaucher C, De Romeuf C. et al. Leu697→Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease. Blood 1994; 83: 1542-50.
24 Obert B, Houllier A, Meyer D. et al. Conformational changes in theA3 domain of von Willebrand factor modulate the interaction of the A1 domain with platelet glycoprotein Ib. Blood 1999; 93: 1959-68.
25 Hommais A, Stepanian A, Fressinaud E. et al. Mutations C1157F and C1234W of von Willebrand factor cause intracellular retention with defective multimerization and secretion. J Thromb Haemost 2006; 04: 148-57.
26 Huizinga EG, Tsuji S, Romijn RAP. et al. Structures of glycoprotein Ib alpha and its complex with von Willebrand factor A1 domain. Science 2002; 297: 1176-9.
27 Howard MA, Perkin J, Salem HH. et al. The agglutination of human platelets by botrocetin: evidence that botrocetin and ristocetin act at different sites on the Factor VIII molecule and platelet membrane. Br J Haematol 1984; 57: 25-35.
28 Christophe O, Ribba AS, Baruch D. et al. Influence of mutations and size of multimers in type II von Willebrand disease upon the function of von Willebrand factor. Blood 1994; 83: 3553-61.
29 Denis CV. Molecular and cellular biology of von Willebrand factor. Int J Hematol 2002; 75: 3-8.