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

Interaction between the platelet glycoprotein Ib alpha (GPIb alpha) receptor and its adhesive ligand von Willebrand factor (VWF) has a critical role in the process of hemostasis. Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder that results from gain-of-function mutations in the GPIBA gene. We studied this gene from 5 members of a previously unreported family with a PT-VWD phenotype. We identified a novel in-frame deletion of 27 base pair (bp) in the macroglycopeptide region. This deletion was not found in the unaffected family members or in 50 healthy controls. The patients' platelets expressed normal quantities of GPIb/IX/V complex on their surface and the mutant (Mut) GPIb alpha was expressed at levels indistinguishable from the wild-type (WT) receptor on the surface of transfected Chinese hamster ovary (CHO) PAX cells. Analysis of ristocetin-mediated I-125-VWF binding showed that the Mut receptor binds VWF in the absence of ristocetin and displays an increased sensitivity to lower concentrations of the modulator. This is the first report of a gain-of-function mutation in the GPIb alpha receptor outside the VWF-binding domain in patients with PT-VWD. The mutation provides a molecular basis for the PT-VWD phenotype and supports a role for the macroglycopeptide region in receptor function.