In an Italian father and son with autosomal dominant platelet-type bleeding disorder-16 and macrothrombocytopenia (BDPLT16; 187800), originally reported by Hardisty et al. (1992), Peyruchaud et al. (1998) identified a heterozygous c.3078G-A transition in the ITGA2B gene, resulting in an arg995-to-gln (R995Q) substitution at a highly conserved GFFKR sequence in the cytoplasmic domain. Expression of the mutation in CHO cells resulted in low surface expression of the mutant protein (about 50%), suggesting that the patient had another pathogenic mutation causing his severe reduction of ITGA2B expression (12-20% of normal). CHO cells transfected with the R995Q mutation showed little or no binding to PAC-1, an antibody that specifically recognizes the activated form of the GPIIb/IIIa complex, suggesting that the mutant complex was not in a high-affinity state. However, incubation with an activating antibody increased PAC-1 binding compared to wildtype, suggesting that the mutant integrin complex is more easily activatable. Peyruchaud et al. (1998) noted that a salt bridge between R995 and residue D723 in the ITGB3 gene (173470) participates in the regulation of the activation state of the complex, and suggested that the R995Q mutation would give rise to a receptor that is not locked in a high activation state, but is more easily activatable compared to wildtype. Nurden et al. (2011) found that the patient reported by Hardisty et al. (1992) and Peyruchaud et al. (1998) also carried a splice site deletion in the ITGA2B gene resulting in lack of protein expression that was inherited from his mother, who had decreased expression of ITGA2B but no platelet abnormalities. This second mutation explained the severe lack of GPIIb/IIIa on the patient's platelets.
