A novel D235Y mutation in the GP1BA gene enhances platelet interaction with von Willebrand factor in an Iranian family with platelet-type von Willebrand disease

Summary

Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder with an intrinsic defect in platelets rather than von Willebrand factor (VWF), but has clinical and laboratory features similar to the more common type 2B VWD. The intriguing nature of the pathophysiology and molecular genetics of PT-VWD has created lengthy debate in literature regarding its discrimination from type 2B VWD, and essentially confirming DNA analysis as the gold standard in diagnosis and revealing pathologic mutations. In this report we identify a novel Asp235Tyr mutation in the GP1BA gene of two Iranian patients showing the PT-VWD phenotype who were originally misdiagnosed as type 2B VWD. By structural modelling of the mutant by introducing Tyr235 into the available crystal structure of the glycoprotein (GP)Ibα N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended β-switch loop of GPIbα. Further modelling of the resulting complex with VWFA1 indicates this could result in an enhanced interface compared to wild-type Asp235. This data provides an update to the present knowledge about this rare disorder, and confirms the necessity of genetic testing for accurate diagnosis, and the importance of studying natural mutations to better understand molecular aspects of GPIbα-VWFA1 interaction.

Keywords

PT-VWD - type 2B VWD - RIPA - platelet function - VWFA1 / GPIbα complex

• References

• 1 Weiss HJ, Meyer D, Rabinowitz R. et al. 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; 306: 326-333.
• 2 Miller JL, Castella A. Platelet-type von Willebrand's disease: characterization of a new bleeding disorder. Blood 1982; 60: 790-794.
• 3 Miller JL. Platelet-type von Willebrand disease. Thromb Haemost 1996; 75: 865-869.
• 4 Othman M. Platelet-type von Willebrand disease and type 2B von Willebrand disease: a story of nonidentical twins when two different genetic abnormalities evolve into similar phenotypes. Semin Thromb Hemost 2007; 33: 780-786.
• 5 Guerrero JA, Kyei M, Russell S. et al. Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation. Blood 2009; 114: 5541-5546.
• 6 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
• 7 Nurden AT. Qualitative disorders of platelets and megakaryocytes. J Thromb Haemost 2005; 3: 1773-1782.
• 8 Hamilton A, Ozelo M, Leggo J. et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 2011; 105: 501-508.
• 9 Othman M, Favaloro EJ. Genetics of type 2B von Willebrand disease: “true 2B”, “tricky 2B”, or “not 2B”. What are the modifiers of the phenotype?. Semin Thromb Hemost 2008; 34: 520-531.
• 10 Favaloro EJ. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin?. Semin Thromb Hemost 2008; 34: 113-127.
• 11 Favaloro EJ, Patterson D, Denholm A. et al. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis. Br J Haematol 2007; 139: 623-626.
• 12 Enayat MS, Guilliatt AM, Lester W. et al. Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importance. Br J Haematol 2006; 133: 664-666.
• 13 Giannini S, Cecchetti L, Mezzasoma AM. et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica 2010; 95: 1021-1024.
• 14 Franchini M, Montagnana M, Lippi G. Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease. Int J Lab Hematol 2008; 30: 91-94.
• 15 Miller JL, Cunningham D, Lyle VA. et al. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. Proc Natl Acad Sci USA 1991; 88: 4761-4765.
• 16 Russell SD, Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood 1993; 81: 1787-1791.
• 17 Takahashi H, Murata M, Moriki T. et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. Blood 1995; 85: 727-733.
• 18 Kunishima S, Heaton DC, Naoe T. et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease. Blood Coagul Fibrinolysis 1997; 8: 311-315.
• 19 Matsubara Y, Murata M, Sugita K. et al. Identification of a novel point mutation in platelet glycoprotein Ibalpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease. J Thromb Haemost 2003; 1: 2198-2205.
• 20 Nurden P, Lanza F, Bonnafous-Faurie C. et al. A second report of platelet-type von Willebrand disease with a Gly233Ser mutation in the GPIBA gene. Thromb Haemost 2007; 97: 319-321.
• 21 Othman M, Notley C, Lavender FL. et al. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 2005; 105: 4330-4336.
• 22 Huizinga EG, Tsuji S, Romijn RA. et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 2002; 297: 1176-1179.
• 23 Murata M, Russell SR, Ruggeri ZM. et al. Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment. J Clin Invest 1993; 91: 2133-2137.
• 24 Moriki T, Murata M, Kitaguchi T. et al. Expression and functional characterization of an abnormal platelet membrane glycoprotein Ib alpha (Met239 --> Val) reported in patients with platelet-type von Willebrand disease. Blood 1997; 90: 698-705.
• 25 Uff S, Clemetson JM, Harrison T. et al. Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation. J Biol Chem 2002; 277: 35657-35663.
• 26 Dumas JJ, Kumar R, McDonagh T. et al. Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations. J Biol Chem 2004; 279: 23327-23334.
• 27 Dong J, Schade AJ, Romo GM. et al. Novel gain-of-function mutations of platelet glycoprotein IBalpha by valine mutagenesis in the Cys209-Cys248 disulfide loop. Functional analysis under statis and dynamic conditions. J Biol Chem 2000; 275: 27663-27670.
• 28 Ware J. Dysfunctional platelet membrane receptors: from humans to mice. Thromb Haemost 2004; 92: 478-485.
• 29 Suva LJ, Hartman E, Dilley JD. et al. Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease. Am J Pathol 2008; 172: 430-439.
• 30 Emsley P, Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystal D 2004; 60: 2126-2132.
• 31 Brunger AT, Adams PD, Clore GM. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystal D 1998; 54: 905-921.
• 32 Wishner BC, Ward KB, Lattman EE. et al. Crystal structure of sickle-cell deoxyhemoglobin at 5 A resolution. J Mol Biol 1975; 98: 179-194.
• 33 Favaloro EJ, Koutts J. 2B or not 2B? Masquerading as von Willebrand disease?. J Thromb Haemost 2012; 10: 317-319.
• 34 O'Connor D, Lester W, Willoughby S. et al. Pregnancy in platelet-type VWD: a case series. Thromb Haemost 2011; 106: 386-387.