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Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK¹ Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, UK² Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, The John Hopkins University, Baltimore, Maryland 21287, USA

(Correspondence should be addressed to A Plagge; Email: a.plagge{at}liv.ac.uk)

The stimulatory -subunit of trimeric G-proteins G_s, which upon ligand binding to seven-transmembrane receptors activates adenylyl cyclases to produce the second messenger cAMP, constitutes one of the archetypal signal transduction molecules that have been studied in much detail. Over the past few years, however, genetic as well as biochemical approaches have led to a range of novel insights into the G_s encoding guanine nucleotide binding protein, -stimulating (Gnas) locus, its alternative protein products and its regulation by genomic imprinting, which leads to monoallelic, parental origin-dependent expression of the various transcripts. Here, we summarise the major characteristics of this complex gene locus and describe the physiological roles of G_s and its ‘extra large’ variant XL_s at post-natal and adult stages as defined by genetic mutations. Opposite and potentially antagonistic functions of the two proteins in the regulation of energy homeostasis and metabolism have been identified in Gnas- and Gnasxl (XL_s)-deficient mice, which are characterised by obesity and leanness respectively. A comparison of findings in mice with symptoms of the corresponding human genetic disease ‘Albright's hereditary osteodystrophy’/‘pseudohypoparathyroidism’ indicates highly conserved functions as well as unresolved phenotypic differences.

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				S. Krechowec and A. Plagge Physiological Dysfunctions Associated with Mutations of the Imprinted Gnas Locus Physiology, August 1, 2008; 23(4): 221 - 229. [Abstract] [Full Text] [PDF]