A Ser162→Leu mutation within glycoprotein (GP) IIIa (integrin β3) results in an unstable αIIIbβ3 complex that retains partial function in a novel form of type II Glanzmann thrombasthenia

Platelets from Glanzmann thrombasthenia patient BL express approximately 30% of the normal alpha(II)beta(3) content and support fibrin-mediated clot retraction, but fail to bind fibrinogen or aggregate following cellular activation. BL platelets bind neither activation-dependent nor activation-independent ligands. DNA sequence analysis of BL platelet mRNA revealed a homozygous C-583-->T point mutation in a conserved region of beta(3). resulting in a Ser162Leu amino acid substitution. This mutation appears to produce destabilizing effects on the alpha(IIb)beta(3) complex, as evidenced by the fact that (1) the BL alpha(IIb)beta(3) complex exhibited altered sedimentation velocity through sucrose gradients, (2) alpha(IIb) and beta(3) was not recognized by complex-dependent monoclonal antibodies or co-precipitated by integrin subunit-specific antibodies, and (3) biosynthesis and trafficking of the alpha(IIb)beta(3)Leu(162) complex was delayed relative to that of the wild-type control. Taken together, these data implicate the region encompassing Ser(162) in the stabilization and ligand binding properties of the alpha(IIb)beta(3) complex.