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

William F. Schwindinger, Alexander Miric, Donald Zimmerman, Michael A. Levine

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Albright hereditary osteodystrophy (AHO) is an autosomal-dominant disorder characterized by decreased expression of Gsα 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 Gsα protein. The R385H substitution is near the carboxyl terminus of the Gsα protein and is located five amino acids upstream of the R389P mutation that uncouples Gsα 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 Gsα cDNAs in COS-1 cells. Neither of the mutant Gsα proteins stimulated adenylyl cyclase in response to l-isoproterenol (1 to 30 μM). By contrast, both mutant Gsα proteins showed activation of adenylyl cyclase in response to forskolin (10 μM) and fluoroaluminate (10 mM). We propose that the R385H mutation produces a Gsα 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.

    Original languageEnglish (US)
    Pages (from-to)25387-25391
    Number of pages5
    JournalJournal of Biological Chemistry
    Volume269
    Issue number41
    StatePublished - Oct 14 1994

    ASJC Scopus subject areas

    • Biochemistry

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