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

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, GPIb, GPIb, GPIX, and GPV, and the coordinated assembly of GPIb, GPIb, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIb gene associated with BSS. Flow cytometric analysis of the patientʹs platelets showed markedly reduced GPIb and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIb was detected; however, GPIb and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIb gene that converts Trp (TGG) to a stop codon (TAG) at residue 123. Transient transfection studies revealed that the mutant GPIb polypeptide was not detected in the transfected 293T cells, suggesting that null expression of the mutant GPIb impairs expression of the GPIb and GPIX subunits and results in a BSS phenotype in the patient. Am. J. Hematol. 71:279-284, 2002.