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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4330-4336.
Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2002-09-2942.
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Submitted September 27, 2002
Accepted December 31, 2004
Identification and functional characterisation of a novel 27bp deletion in the macroglycopeptide-coding region of the GPIb gene resulting in platelet-type von Willebrand disease
Maha Othman, Colleen Notley, Frances L Lavender, Helen White, Christopher D Byrne, David Lillicrap, and Denise F O'Shaughnessy*
Department of Pathology and Molecular Medicine, Queens University, Kingston, Canada
Molecular Pathology Unit, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
Department of Endocrinology and Metabolism, Southampton University Hospital NHS Trust, Southampton, United Kingdom
Department of Hematology, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
* Corresponding author; email: kcb07{at}dial.pipex.com.
Interaction between the platelet GPIb receptor and its adhesive ligand von Willebrand factor 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 GPIb gene. We studied this gene from five members of a previously unreported family with a platelet-type VWD phenotype. We identified a novel in-frame deletion of 27 bp in the macroglycopeptide region. This deletion was not found in the non affected family members or in 50 normal controls. The patients' platelets expressed normal quantities of GPIb/IX/V complex on their surface and the mutant (Mut) GPIbwas expressed at levels indistinguishable from the wild type (WT) receptor on the surface of transfected CHO  /IX cells. Analysis of ristocetin-mediated 125 I- 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 receptor out side 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.
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