A novel G_sα mutant in a patient with albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase

Albright hereditary osteodystrophy (AHO) is an autosomal-dominant disorder characterized by decreased expression of G_sα and widespread tissue resistance to hormones that activate adenylyl cyclase. We identified a single mutation, R385H, in the G₂α gene of a subject with AHO who had evidence for a dysfunctional G_sα protein. The R385H substitution is near the carboxyl terminus of the G_sα protein and is located five amino acids upstream of the R389P mutation that uncouples G_sα from cell surface receptors in the une clone of S49 murine lymphoma. To test the biological activity of the R385H mutant, we transiently expressed wild type, R385H, and R389P G_sα cDNAs in COS-1 cells. Neither of the mutant G_sα proteins stimulated adenylyl cyclase in response to l-isoproterenol (1 to 30 μM). By contrast, both mutant G_sα proteins showed activation of adenylyl cyclase in response to forskolin (10 μM) and fluoroaluminate (10 mM). We propose that the R385H mutation produces a G_sα molecule that is unable to interact with hormone receptors and results in uncoupling of adenylyl cyclase from cell surface receptors. This uncoupling mutation represents a new type of molecular defect that can result in AHO.