Novel nonsense mutation in the platelet glycoprotein Ibβ gene associated with Bernard-Soulier syndrome

Abstract

Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder caused by quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbα, GPIbβ, GPIX, and GPV, and the coordinated assembly of GPIbα, GPIbβ, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIbβ gene associated with BSS. Flow cytometric analysis of the patient's platelets showed markedly reduced GPIbα and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIbα was detected; however, GPIbβ and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIbβ gene that converts Trp (TGG) to a stop codon (TAG) at residue 123. Transient transfection studies revealed that the mutant GPIbβ polypeptide was not detected in the transfected 293T cells, suggesting that null expression of the mutant GPIbβ impairs expression of the GPIbα and GPIX subunits and results in a BSS phenotype in the patient. © 2002 Wiley-Liss, Inc.