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Molecular and clinical characteristics of the McCune–Albright syndrome 

Molecular and clinical characteristics of the McCune–Albright syndrome
Molecular and clinical characteristics of the McCune–Albright syndrome

Steven A. Lietman

and Michael A. Levine

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date: 17 May 2022

Heterotrimeric guanine nucleotide-binding proteins (G proteins) couple extracellular receptor proteins to intracellular effector enzymes and ion channels. The observation that alterations in G protein-coupled signalling pathways can impact cellular function and proliferation, and cause human disease, has stimulated investigation into the molecular and pharmacological regulation of G protein expression and action. The most well characterized models for altered G protein expression defects have been based on naturally occurring mutations in GNAS, a complex gene at 20q13 which encodes the α‎ subunit of Gs, the G protein that stimulates adenylyl cyclase. Somatic mutations in GNAS (OMIM 139320) that activate Gα‎s are present in a subset of endocrine tumours and in patients with the McCune–Albright syndrome (OMIM 174800), a sporadic disorder characterized by increased hormone production and/or cellular proliferation of many tissues. By contrast, germline mutations of the GNAS gene that decrease expression or function of Gα‎s are present in subjects with Albright’s hereditary osteodystrophy (AHO), a heritable disorder associated with a constellation of developmental defects and, in many patients, reduced responsiveness to multiple hormones that signal through receptors that require Gα‎s to activate adenylyl cyclase EC (i.e. pseudohypoparathyroidism type 1a (OMIM 103580)). McCune–Albright syndrome (MAS) and AHO represent contrasting gain of function and loss of function mutations in the GNAS gene, respectively. Clinical and biochemical analyses of subjects with these syndromes have extended our understanding of the developmental and functional consequences of dysfunctional G protein action, and have provided unexpected insights into the importance of cAMP as a regulator of the growth and/or function of many tissues. This chapter will focus on the clinical implications of activating mutations of GNAS as the basis for MAS.

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