Thromb Haemost 2001; 86(03): 848-854
DOI: 10.1055/s-0037-1616142
Review Articles
Schattauer GmbH

Ser968Thr Mutation within the A3 Domain of Von Willebrand Factor (VWF) in Two Related Patients Leads to a Defective Binding of VWF to Collagen

Anne-Sophie Ribba*
,
Irmine Loisel*
,
Jean-Maurice Lavergne
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
,
Irène Juhan-Vague
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
,
Bernadette Obert
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
,
Ghislaine Cherel
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
,
Dominique Meyer
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
,
Jean-Pierre Girma
1   INSERM U 143, Hôpital de Bicêtre, Paris, CHU La Timone, Marseille, France
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Publikationsverlauf

Received 11. Juli 2000

Accepted after resubmission 07. Mai 2001

Publikationsdatum:
14. Dezember 2017 (online)

Summary

We report the identification of a new mutation of von Willebrand Factor (VWF) gene within exon 30 occurring in two related patients (mother and daughter) with a hemorrhagic syndrome. A T A transvertion at nucleotide 5441 was found changing the serine 968 to threonine of the mature VWF subunit (S1731T of the preproVWF). The Ser968Thr mutation is located within the VWF A3 domain which interacts with type I and III collagens. Both patients were found to be heterozygous for the mutation. The propositus (daughter) exhibited a slightly prolonged bleeding time, levels of VWF:Ag and VWF:RCo at the lower limit of normal, contrasting with normal levels of VIII:C. Her mother exhibited borderline bleeding time and moderately decreased levels of VWF and VIII:C. In both patients multimeric structure of VWF and ristocetin- as well as botrocetin-induced binding of VWF to GPIb were normal; however both patients repeatedly showed decreased binding of VWF to collagen. The Ser968Thr substitution was reproduced by site-directed mutagenesis on the full-length cDNA of VWF. The mutated recombinant VWF (rVWF), T968rVWF, and the hybrid S/T968rVWF were transiently expressed by COS-7 cells. Both rVWF exhibited normal multimeric pattern and normal ristocetin- as well as botrocetin-induced binding to GPIb. T968rVWF showed significantly decreased binding to collagen while the hybrid S/T968rVWF bound to collagen in a similar way to that of the patients’ plasma VWF. Thus, our data demonstrate that the Ser968Thr mutation of the VWF A3 domain is clearly responsible for the abnormal binding of VWF to collagen observed in both patients. The Ser968Thr substitution of the VWF is the first mutation identified in two patients leading to a decreased affinity of VWF for collagen and a normal multimeric structure.

* ASR and IL contributed equally to this work.


 
  • References

  • 1 Sadler JE. Biochemistry and genetics of von Willebrand factor. Ann Rev Biochem 1998; 67: 395-424.
  • 2 Bockenstedt P, Mcdonagh J, Handin RI. Binding and covalent cross-linking of purified von willebrand factor to native monomeric collagen. J Clin Invest 1986; 78: 551-6.
  • 3 Rand JH, Patel ND, Schwartz E, Zhou SL, Potter BJ. 150-kD von Wille-brand factor binding protein extracted from human vascular subendothelium is Type-VI collagen. J Clin Invest 1991; 88: 253-9.
  • 4 Denis C, Baruch D, Kielty CM, Ajzenberg N, Christophe O, Meyer D. Localization of von Willebrand factor binding domains to endothelial extracellular matrix and to Type-VI collagen. Arterioscler Thromb 1993; 13: 398-406.
  • 5 Ross JM, Mcintire LV, Moake JL, Rand JH. Platelet adhesion and aggregation on human type VI collagen surfaces under physiological flow conditions. Blood 1995; 85: 1826-35.
  • 6 Pareti FI, Niiya K, McPherson JM, Ruggeri ZM. Isolation and characterization of two domains of human von Willebrand Factor that interact with fibrillar collagen types I and III. J Biol Chem 1987; 262: 13835-41.
  • 7 Girma JP, Kalafatis M, Pietu G, Lavergne JM, Chopek MW, Edgington TS, Meyer D. Mapping of distinct von Willebrand Factor domains interacting with platelet GPIb and GPIIb/IIIa and with collagen using monoclonal antibodies. Blood 1986; 67: 1356-66.
  • 8 Kalafatis M, Takahashi Y, Girma JP, Meyer D. Localization of a collagen-interactive domain of human von Willebrand Factor between amino acid residues Gly 911 and Glu 1365. Blood 1987; 70: 1577-83.
  • 9 Roth GJ, Titani K, Hoyer LW, Hickey MJ. Localization of binding sites within human von Willebrand Factor for monomeric type III collagen. Biochemistry 1986; 25: 8357-61.
  • 10 Hoylaerts MF, Yamamoto H, Nuyts K, Vreys I, Deckmyn H, Vermylen J. von Willebrand factor binds to native collagen VI primarily via its A1 domain. Biochem J 1997; 324: 185-91.
  • 11 Mazzucato M, Spessotto P, Masotti A, DeAppollonia L, Cozzi MR, Yoshioka A, Perris R, Colombatti A, DeMarco L. Identification of domains responsible for von Willebrand factor type VI collagen interaction mediating platelet adhesion under high flow. J Biol Chem 1999; 274: 3033-41.
  • 12 Sixma JJ, Schiphorst ME, Verweij CL, Pannekoek H. Effect of deletion of the A1-domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin. Eur J Biochem 1991; 196: 369-75.
  • 13 Lankhof H, Vanhoeij M, Schiphorst ME, Bracke M, Wu YP, Ijsseldijk MJ, Vink T, de Groot PG, Sixma JJ. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75: 950-8.
  • 14 Cruz MA, Yuan HB, Lee JR, Wise RJ, Handin RI. Interaction of the von Willebrand factor (VWF) with collagen – Localization of the primary collagen-binding site by analysis of recombinant vWF A domain polypeptides. J Biol Chem 1995; 270: 10822-7.
  • 15 Huizinga EG, vander Plas RM, Kroon J, Sixma JJ, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 5: 1147-56.
  • 16 Bienkowska J, Cruz M, Atiemo A, Handin R, Liddington R. The von Wille-brand factor A3 domain does not contain a metal ion-dependent adhesion site motif. J Biol Chem 1997; 272: 25162-7.
  • 17 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
  • 18 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.
  • 19 Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand Factor. Cleavage is present in normal individuals, increased in type IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest 1986; 77: 947-51.
  • 20 Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6306-10.
  • 21 Federici AB, Bader R, Pagani S, Colibretti ML, De Marco L, Mannucci PM. Binding of von Willebrand Factor to glycoproteins Ib and IIb/IIIa complex: affinity is related to multimeric size. Br J Haematol 1989; 73: 93-9.
  • 22 Favaloro EJ, Grispo L, Exner T, Koutts J. Development of a simple collagen based ELISA assay aids in the diagnosis of, and permits sensitive discrimination between Type I and Type II von Willebrand’s disease. Blood Coagul Fibrinolysis 1991; 2: 285-91.
  • 23 Veyradier A, Jumilly AL, Ribba AS, Obert B, Houllier A, Meyer D, Girma JP. New assay for measuring binding of platelet glycoprotein IIb/IIIa to unpurified von Willebrand factor. Thromb Haemost 1999; 82: 134-9.
  • 24 Veyradier A, Fressinaud E, Meyer D. Laboratory diagnosis of von Willebrand disease. Intern J Clin Lab Res 1998; 28: 201-10.
  • 25 Ribba AS, Lavergne JM, Bahnak BR, Derlon A, Pietu G, Meyer D. Duplication of a methionine within the glycoprotein Ib binding domain of von Willebrand Factor detected by denaturing gradient gel electrophoresis in a patient with type-IIB von Willebrand Disease. Blood 1991; 78: 1738-43.
  • 26 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-27.
  • 27 Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Lebeau 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.
  • 28 Hilbert L, Gaucher C, Mazurier C. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (vWF) responsible for type 2 von Willebrand disease with decreased platelet-dependent function of vWF. Blood 1995; 86: 1010-8.
  • 29 Obert B, Houllier A, Meyer D, Girma JP. Conformational changes in the A3 domain of von Willebrand factor modulate the interaction of the A1 domain with platelet glycoprotein Ib. Blood 1999; 93: 1959-68.
  • 30 Meyer D, Zimmerman TS, Obert B, Edgington TS. Hybridoma antibodies to human von Willebrand Factor. I. Characterization of seven clones. Br J Haematol 1984; 57: 597-608.
  • 31 Obert B, Tout H, Veyradier A, Fressinaud E, Meyer D, Girma JP. Estimation of the von Willebrand factor-cleaving protease in plasma using monoclonal antibodies to vWF. Thromb Haemost 1999; 82: 1382-5.
  • 32 Nishikubo T, Christophe O, Lavergne JM, Obert B, Nonami K, Takahashi Y, Yoshioka A, Meyer D, Girma JP. Abnormal proteolytic processing of von Willebrand Factor Arg611Cys and Arg611His. Thromb Haemost 1997; 77: 174-82.
  • 33 Siguret V, Ribba AS, Christophe O, Cherel G, Obert B, Rouault C, Nishikubo T, Meyer D, Girma JP, Pietu G. Characterization of recombinant von Willebrand factors mutated on cysteine 509 or 695. Thromb Haemost 1996; 76: 453-9.
  • 34 Casonato A, Pontara E, Bertomoro A, Zucchetto S, Zerbati S, Girolami A. Abnormal collagen binding activity of 2A von Willebrand factor: Evidence that the defect depends only on the lack of large multimers. J Lab Clin Med 1997; 129: 251-9.
  • 35 Lankhof H, Damas C, Schiphorst ME, Ijsseldijk MJW, Bracke M, Sixma JJ, Vink T, de Groot PG. Functional studies on platelet adhesion with recombinant von Willebrand factor type 2B mutants R543Q and R543W under conditions of flow. Blood 1997; 89: 2766-72.
  • 36 Lankhof H, Damas C, Schiphorst ME, Ijsseldijk MJW, Bracke M, Furlan M, de Groot PG, Sixma JJ, Vink T. 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.
  • 37 Casonato A, Pontara E, Bertomoro A, Sartorello F, Girolami A. Which assay is the most suitable to investigate von Willebrand factor functional activity?. Thromb Haemost 1999; 81: 994-5.
  • 38 Hillery CA, Mancuso DJ, Sadler JE, Ponder JW, Jozwiak MA, Christopher-son PA, Gill JC, Scott JP, Montgomery RR. Type 2M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin – but not botrocetin-mediated binding of von Willebrand factor to platelets. Blood 1998; 91: 1572-81.
  • 39 Zieger B, Budde U, Jessat U, Zimmermann R, Simon M, Katzel R, Sutor AH. New families with von Willebrand disease type 2M (Vicenza). Thromb Res 1997; 87: 57-64.
  • 40 Favaloro EJ, Koutts J. Laboratory assays for von Willebrand factor: Relative contribution to the diagnosis of von Willebrand’s disease. Pathology 1997; 29: 385-91.