Identification of a novel point mutation in platelet glycoprotein Ibα Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease

Background: Interaction between platelet glycoprotein (GP)Ibalpha and von Willebrand factor (VWF) has critical roles in both physiological hemostasis and thrombosis. Platelet-type von Willebrand disease (plt-VWD) is a congenital bleeding disorder characterized by gain-of-function mutations of GPIbalpha. To date, two mutations in GPIbalpha, G233V and M239V, have been reported in four unrelated families with plt-VWD. Objective: The present study aimed to determine whether G233S of GPIbalpha, a new mutation observed in plt-VWD patients, causes the plt-VWD phenotype and to examine whether conversions to other residues at this position affect VWF binding. Patients and methods: The propositus was a 3-year-old Japanese male. He displayed bleeding symptoms and moderate thrombocytopenia. His brother was similarly affected. Platelets from both patients were analyzed by ristocetin- or shear-induced platelet aggregation. DNA sequencing was performed to analyze the GPIbalpha sequence. We examined the I-125-labeled VWF binding using a series of recombinant GPIba fragments with different residues at position 233 (G233S, G233A, G233K, and G233D) together with naturally occurring mutations previously reported in patients (G233V and M239V). Results: Platelet function analysis indicated that platelets from both patients had a typical plt-VWD phenotype. DNA sequencing analysis showed a heterozygous mutation of Gly to Set at residue 233 of GPIbalpha in both patients. The I-125-labeled VWF binding to mutant compared with the wild type displayed three patterns, gain-of-function (G233S, G233V, and M239V), equivalent function (G233A), and loss-of-function (G233K and G233D). Conclusions: The G233S is a molecular basis of plt-VWD, and residue 233 plays critical roles in regulating VWF binding.