title: Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy.
abstract: Albright's hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression or function of the alpha subunit of the stimulatory G protein (Gs alpha) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. We identified a unique Gs alpha protein in erythrocytes from two related patients with Albright's hereditary osteodystrophy and reduced Gs alpha bioactivity. The Gs alpha variant was recognized by a carboxyl terminal-specific Gs alpha antiserum but not by polyclonal antiserums specific for the amino terminus of Gs alpha. To investigate the molecular basis for this structurally abnormal Gs alpha protein, we studied the Gs alpha gene by restriction-endonuclease analysis. DNA from the two patients had an abnormal restriction-fragment pattern when digested with Ncol, which was consistent with loss of an Ncol restriction site in exon 1 of one Gs alpha allele. Amplification of a 260-base-pair region that includes exon 1 of the Gs alpha gene and direct sequencing of the amplified DNA revealed an A-to-G transition at position +1 in one Gs alpha allele from each of the two patients. This mutation converts the initiator ATG (methionine) codon to GTG (valine), blocking initiation of translation at the normal site. Translation of the abnormal Gs alpha messenger RNA would result in the synthesis of a truncated Gs alpha molecule lacking the amino terminus. We conclude that in at least some patients with Albright's hereditary osteodystrophy, the disease is caused by a single-base substitution in the Gs alpha gene and is thus due to an inherited mutation in a human G protein.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: J L
authors.initials: JL
authors.lastname: Patten
authors.forename: D R
authors.initials: DR
authors.lastname: Johns
authors.forename: D
authors.initials: D
authors.lastname: Valle
authors.forename: C
authors.initials: C
authors.lastname: Eil
authors.forename: P A
authors.initials: PA
authors.lastname: Gruppuso
authors.forename: G
authors.initials: G
authors.lastname: Steele
authors.forename: P M
authors.initials: PM
authors.lastname: Smallwood
authors.forename: M A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004247:DNA / Q000032:analysis; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005796:Genes; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D004247:DNA; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases