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

作者：Enayat Said; Ravanbod Shirin; Rassoulzadegan Maryam; Jazebi Mohammad; Tarighat Shirin; Ala Fereydoun; Emsley Jonas; Othman Maha^*

来源：Thrombosis and Haemostasis, 2012, 108(5): 946-954.

DOI：10.1160/TH12-04-0189

• PT-VWD
• type 2B VWD
• RIPA
• platelet function
• VWFA1 / GPIb alpha complex

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)Ib alpha N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended beta-switch loop of GPIb alpha. 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 GPIb alpha-VWFA1 interaction.

• 出版日期2012-11