title: Clinical implications of genetic defects in G proteins: oncogenic mutations in G alpha s as the molecular basis for the McCune-Albright syndrome.
abstract: Signal-transducing guanine nucleotide-binding proteins (G proteins) couple extracellular receptor proteins to intracellular effector enzymes and ion channels, and therefore are critical mediators of cellular responses to external stimuli. G proteins are comprised of three subunits (alpha, beta, gamma), each encoded by many different genes. The multiplicity of G protein subunits facilitates great combinatorial variability, which, in part, accounts for the ability of G proteins to interact with many different receptor and effector proteins. Hundreds of G protein-coupled receptors have been identified, and their unique patterns of expression among a restricted number of cell types contributes greatly to the apparent specificity of hormone action. Mutations that either activate or inactivate some of these receptors account for a number of highly specific syndromes, which affect a limited number of target tissues. By contrast, most G proteins are widely expressed in many tissues. Accordingly, mutations in these signaling molecules would be expected to produce a more generalized pattern of hormone dysfunction. Activating mutations in the gene (GNAS1) that encode the alpha subunit of the G protein that stimulates adenylyl cyclase (AC) have been identified in many endocrine neoplasms and diverse tissues of patients with McCune-Albright syndrome. The McCune-Albright syndrome is characterized by autonomous endocrine function, hyperpigmented skin lesions, and fibrous dysplasia of bone--effects which reflect the ability of CAMP to stimulate cell function and proliferation in a wide variety of tissues. The unusual features of the McCune-Albright syndrome are explained by the mosaic distribution of cells bearing the mutant allele, an observation that is most consistent with postzygotic mutation of GNAS1. Experimental analysis of this syndrome has extended our understanding of the clinical and biochemical consequences of dysfunctional G protein action and has provided a bench-to-bedside demonstration of the critical role that G proteins play in transmembrane signal transduction in humans.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. mlevine@jhu.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000818:Animals; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics* / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics*
chemical_list: D015513:Oncogene Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs