Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.

Abstract

Recent advances in molecular genetics have revealed the mechanisms underlying a variety of inherited human disor- ders. Among them, mutations in G protein-coupled recep- tors have clearly demonstrated two types of abnormalities, namely loss of function and constitutive activation of the receptors. Thromboxane A2(TXA2) receptor is a member of the family of G protein-coupled receptors and performs an essential role in hemostasis by interacting with TXA2 to induce platelet aggregation. Here we identify a single amino acid substitution (Arg4-Leu) in the first cytoplasmic loop of the TXA2 receptor in a dominantly inherited bleeding disorder characterized by defective platelet response to TXA2. 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 forma- tion despite its normal ligand binding affinities. These re- sults suggest that the Arg'0 to Leu mutation is responsible for the disorder. Moreover, dominant inheritance of the disorder suggests the possibility that the mutation produces a dominant negative TXA2 receptor. (J. Clin. Invest. 94:1662-1667.) Key words: G protein * blood platelets phospholipase C * human genetics * point mutation Introduction