Clinical implications of genetic defects in G proteins: Oncogenic mutations in G alpha(s) as the molecular basis for the McCune-Albright syndrome

Signal-transducing guanine nucleotide-binding proteins (G proteins) couple extracellular receptor proteins to intracellular effector enzymes and ion c hannels, and therefore Lire critical mediators of cellular responses to ext ernal stimuli. G proteins are comprised of three subunits (alpha, beta, gam ma), each encoded by many different genes. The multiplicity of G protein su bunits facilitates great combinatorial variability, which, in part, account s for the ability of G proteins to interact with many different receptor an d effector proteins. Hundreds of C protein-coupled receptors have been iden tified, and their unique patterns of expression among a restricted number o f cell types contributes greatly to the apparent specificity of hormone act ion. Mutations that either activate or inactivate some of these receptors a ccount for a number of highly specific syndromes, which affect a limited nu mber of target tissues. By contrast, most G proteins are widely expressed i n many tissues. Accordingly, mutations in these signaling molecules would b e expected to produce a more generalized pattern of hormone dysfunction. Ac tivating mutations in the gene (GNAS1) that encode the or 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 sy ndrome. The McCune-Albright syndrome is characterized by autonomous endocri ne function, hyperpigmented skin lesions, and fibrous dysplasia of bone-eff ects which reflect the ability of CAMP to stimulate cell function and proli feration in a wide variety of tissues. The unusual features of the McCune-A lbright 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. (C) 2000 IMSS. Published by Elsevier Science Inc.