title: A novel Gs alpha mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase.
abstract: Albright hereditary osteodystrophy (AHO) is an autosomal-dominant disorder characterized by decreased expression of Gs alpha and widespread tissue resistance to hormones that activate adenylyl cyclase. We identified a single mutation, R385H, in the Gs alpha gene of a subject with AHO who had evidence for a dysfunctional Gs alpha protein. The R385H substitution is near the carboxyl terminus of the Gs alpha protein and is located five amino acids upstream of the R389P mutation that uncouples Gs alpha from cell surface receptors in the unc clone of S49 murine lymphoma. To test the biological activity of the R385H mutant, we transiently expressed wild type, R385H, and R389P Gs alpha cDNAs in COS-1 cells. Neither of the mutant Gs alpha proteins stimulated adenylyl cyclase in response to l-isoproterenol (1 to 30 microM). By contrast, both mutant Gs alpha proteins showed activation of adenylyl cyclase in response to forskolin (10 microM) and fluoroaluminate (10 mM). We propose that the R385H mutation produces a Gs 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.
authors.affiliation: Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: W F
authors.initials: WF
authors.lastname: Schwindinger
authors.forename: A
authors.initials: A
authors.lastname: Miric
authors.forename: D
authors.initials: D
authors.lastname: Zimmerman
authors.forename: M A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000535:Aluminum / Q000494:pharmacology; D001483:Base Sequence; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D004910:Erythrocyte Membrane / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005461:Fluorine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000235:genetics*; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011547:Pseudohypoparathyroidism / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003062:Codon; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D005576:Colforsin; C053629:fluoroaluminum; D005461:Fluorine; D000535:Aluminum; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine