ARG(60) TO LEU MUTATION OF THE HUMAN THROMBOXANE A(2) RECEPTOR IN A DOMINANTLY INHERITED BLEEDING DISORDER

Recent advances in molecular genetics have revealed the mechanisms underlying a variety of inherited human disorders. Among them, mutations in G protein-coupled receptors have clearly demonstrated two types of abnormalities, namely loss of function and constitutive activation of the receptors. Thromboxane A(2)(TXA(2)) receptor is a member of the family of G protein-coupled receptors and performs an essential role in hemostasis by interacting with TXA(2) to induce platelet aggregation. Here we identify a single amino acid substitution (Arg(60)-->Leu) in the first cytoplasmic loop of the TXA(2) receptor in a dominantly inherited bleeding disorder characterized by defective platelet response to TXA(2). This mutation was found exclusively in affected members of two unrelated families with the disorder. The mutant receptor expressed in Chinese hamster ovary cells showed decreased agonist-induced second messenger formation despite its normal ligand binding affinities. These results suggest that the Arg(60) to Leu mutation is responsible for the disorder. Moreover, dominant inheritance of the disorder suggests the possibility that the mutation produces a dominant negative TXA(2) receptor.