title: 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.
abstract: 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 Asp235Tyrmutation 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.
authors.affiliation: Iranian Comprehensive Haemophilia Care Centre, Tehran, Islamic Republic of Iran.
authors.forename: Said
authors.initials: S
authors.lastname: Enayat
authors.forename: Shirin
authors.initials: S
authors.lastname: Ravanbod
authors.forename: Maryam
authors.initials: M
authors.lastname: Rassoulzadegan
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jazebi
authors.forename: Shirin
authors.initials: S
authors.lastname: Tarighat
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Ala
authors.forename: Jonas
authors.initials: J
authors.lastname: Emsley
authors.forename: Maha
authors.initials: M
authors.lastname: Othman
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001792:Blood Platelets / Q000502:physiology*; D003951:Diagnostic Errors; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000502:physiology; D005260:Female; D020690:GTPase-Activating Proteins; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood* / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D019038:Platelet Glycoprotein GPIb-IX Complex; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D029701:Saccharomyces cerevisiae Proteins; D014842:von Willebrand Diseases / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D014841:von Willebrand Factor / Q000737:chemistry / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D020690:GTPase-Activating Proteins; C064960:IRA2 protein, S cerevisiae; D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D029701:Saccharomyces cerevisiae Proteins; C460760:VWA1 protein, human; C094990:adhesion receptor; D014841:von Willebrand Factor