A novel polymorphism, ⁷⁰Leu/Phe, disrupts a consensus Leu residue within the leucine-rich repeat sequence of platelet glycoprotein Ibα

Platelet glycoprotein (GP) Ib/IX/V complex mediates high-shear dependent platelet activation through an interaction with the von Willebrand factor (vWF). All four subunits of the complex have a structural motif, the leucine-rich repeat (LRR) sequence, with leucines in conserved positions. Here we report a new polymorphism, Leu/Phe at residue 70 of GPIbα, which disrupts the consensus sequence of the LRR in the vWF binding domain. Genotype frequencies among 142 healthy Japanese subjects were 92.3%, 7.7%, and 0.0%, for the ⁷⁰Leu/Leu, ⁷⁰Leu/Phe, and ⁷⁰Phe/Phe genotypes, respectively. Ristocetin-induced or shear-induced platelet aggregation was not significantly different between the ⁷⁰Leu/Leu and ⁷⁰Leu/Phe genotypes. In in vitro studies, a recombinant GPIbα fragment with ⁷⁰Phe (L70F) as compared to that with ⁷⁰Leu (WT) had low reactivity to anti-GPIbα monoclonal antibodies, GUR20-5 and Hip1, both of which recognize conformation-specific epitopes within the 45-kDa domain. Ristocetin-induced ¹²⁵I-vWF binding to L70F, however, did not differ from that to WT.