A NOVEL G(S)ALPHA MUTANT IN A PATIENT WITH ALBRIGHT HEREDITARY OSTEODYSTROPHY UNCOUPLES CELL-SURFACE RECEPTORS FROM ADENYLYL-CYCLASE

作者：SCHWINDINGER WF; MIRIC A; ZIMMERMAN D; LEVINE MA

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 1994, 269(41): 25387-25391.

DOI：10.1016/s0021-9258(18)47261-4

Albright hereditary osteodystrophy (AHO) is an autosomal-dominant disorder characterized by decreased expression of G(s) alpha and widespread tissue resistance to hormones that activate adenylyl cyclase. We identified a single mutation, R385H, in the G(s) alpha gene of a subject with AHO who had evidence for a dysfunctional G(s) alpha protein. The R385H substitution is near the carboxyl terminus of the G(s) alpha protein and is located five amino acids upstream of the R389P mutation that uncouples G(s) alpha 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(s) alpha cDNAs in COS-1 cells. Neither of the mutant G(s) alpha proteins stimulated adenylyl cyclase in response to l-isoproterenol (1 to 30 mu M). By contrast, both mutant G(s) alpha proteins showed activation of adenylyl cyclase in response to forskolin (10 mu M) and fluoroaluminate (10 mM). We propose that the R385H mutation produces a G(s) alpha 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.

• 出版日期1994-10-14