Novel heterozygous missense mutation in the platelet glycoprotein Ibβ gene associated with isolated giant platelet disorder

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Abstract
The glycoprotein (GP) Ib/IX/V complex plays an important role in primary hemostasis, serving as the platelet receptor for von Willebrand factor (vWF). Recent studies have shown that the phenotype caused by mutations in the subunits of the GPIb/IX complex spans a wide spectrum; from the normal phenotype, to isolated giant platelet disorders (GPD), and to the full‐blown bleeding disorder, the Bernard‐Soulier syndrome (BSS). We characterize here a novel missense mutation of the GPIbβ gene associated with isolated GPD. In the patient's platelets, the expression level of the GPIb/IX complex was moderately reduced compared with that of the GPIIb/IIIa complex, whereas the latter was expressed at higher levels than in a normal control. Immunoblot analysis showed normal electrophoretic mobility of GPIbα, GPIbβ, and GPIX. However, the amount of GPIbβ was approximately 66% of the normal value. DNA sequencing analysis revealed a novel heterozygous missense mutation in the GPIbβ gene that converts Arg (CGC) to Cys (TGC) at residue 17. Transient transfection studies demonstrated that mutant GPIbβ protein was not detected in transfected 293T cells. These findings indicated that null expression of the abnormal GPIbβ causes decreased expression of the complex and results in the GPD phenotype in the patient, and suggested that homozygosity of the mutation may lead to a BSS phenotype in vivo. Am. J. Hematol. 68:249–255, 2001.