G protein mutations in endocrine diseases

Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, University of Milan, Via F. Sforza 35, 20122 Milan, Italy.

This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identified which harbor naturally occurring mutations, Gsalpha, the activator of adenylyl cyclase and Gi2alpha, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsalpha (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-specific hormone resistance observed in PHP Ia may result from tissue-specific imprinting of the GNAS1 gene, although the Gsalpha knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsalpha mutations leading to cell proliferation have been identified in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune-Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2alpha have been identified in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and significance are still controversial. Finally, although Galpha subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, beta/gamma subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of beta3 subunit variants in patients with essential hypertension.

This article has been cited by other articles:

				L. I. Jiang, J. Collins, R. Davis, I. D. Fraser, and P. C. Sternweis Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII J. Biol. Chem., August 22, 2008; 283(34): 23429 - 23439. [Abstract] [Full Text] [PDF]

				C Vincent-Dejean, L Cazabat, L Groussin, K Perlemoine, G Fumey, F Tissier, X Bertagna, and J Bertherat Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity. Eur. J. Endocrinol., June 1, 2008; 158(6): 829 - 839. [Abstract] [Full Text] [PDF]

				P. S. H. Soon, K. L. McDonald, B. G. Robinson, and S. B. Sidhu Molecular Markers and the Pathogenesis of Adrenocortical Cancer Oncologist, May 1, 2008; 13(5): 548 - 561. [Abstract] [Full Text] [PDF]

				R. B. Penn and J. L. Benovic Regulation of Heterotrimeric G Protein Signaling in Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 47 - 57. [Abstract] [Full Text] [PDF]

				G. Mantovani, S. Bondioni, A. Linglart, M. Maghnie, M. Cisternino, S. Corbetta, A. G. Lania, P. Beck-Peccoz, and A. Spada Genetic Analysis and Evaluation of Resistance to Thyrotropin and Growth Hormone-Releasing Hormone in Pseudohypoparathyroidism Type Ib J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3738 - 3742. [Abstract] [Full Text] [PDF]

				D. Romano, K. Magalon, M. Pertuit, R. Rasolonjanahary, A. Barlier, A. Enjalbert, and C. Gerard Conditional Overexpression of the Wild-Type Gs{alpha} as the gsp Oncogene Initiates Chronic Extracellularly Regulated Kinase 1/2 Activation and Hormone Hypersecretion in Pituitary Cell Lines Endocrinology, June 1, 2007; 148(6): 2973 - 2983. [Abstract] [Full Text] [PDF]

				L. I. Jiang, J. Collins, R. Davis, K.-M. Lin, D. DeCamp, T. Roach, R. Hsueh, R. A. Rebres, E. M. Ross, R. Taussig, et al. Use of a cAMP BRET Sensor to Characterize a Novel Regulation of cAMP by the Sphingosine 1-Phosphate/G13 Pathway J. Biol. Chem., April 6, 2007; 282(14): 10576 - 10584. [Abstract] [Full Text] [PDF]

				J. Xu, J. Tian, S. M. Grumelli, K. J. Haley, and S. D. Shapiro Stage-specific Effects of cAMP Signaling during Distal Lung Epithelial Development J. Biol. Chem., December 15, 2006; 281(50): 38894 - 38904. [Abstract] [Full Text] [PDF]

				G. Mantovani, S. Bondioni, S. Ferrero, B. Gamba, E. Ferrante, E. Peverelli, S. Corbetta, M. Locatelli, P. Rampini, P. Beck-Peccoz, et al. Effect of Cyclic Adenosine 3',5'-Monophosphate/Protein Kinase A Pathway on Markers of Cell Proliferation in Nonfunctioning Pituitary Adenomas J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6721 - 6724. [Abstract] [Full Text] [PDF]

				N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]

				S. M. Assmann Plant G Proteins, Phytohormones, and Plasticity: Three Questions and a Speculation Sci. Signal., December 21, 2004; 2004(264): re20 - re20. [Abstract] [Full Text] [PDF]

				A. G. Lania, G. Mantovani, S. Ferrero, C. Pellegrini, S. Bondioni, E. Peverelli, P. Braidotti, M. Locatelli, M. L. Zavanone, E. Ferrante, et al. Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein Cancer Res., December 15, 2004; 64(24): 9193 - 9198. [Abstract] [Full Text] [PDF]

				G. Mantovani, S. Bondioni, M. Locatelli, C. Pedroni, A. G. Lania, E. Ferrante, M. Filopanti, P. Beck-Peccoz, and A. Spada Biallelic Expression of the Gs{alpha} Gene in Human Bone and Adipose Tissue J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6316 - 6319. [Abstract] [Full Text] [PDF]

				S. Lumbroso, F. Paris, and C. Sultan Activating Gs{alpha} Mutations: Analysis of 113 Patients with Signs of McCune-Albright Syndrome--A European Collaborative Study J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2107 - 2113. [Abstract] [Full Text] [PDF]

				A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]

				G. Mantovani, M. Maghnie, G. Weber, E. De Menis, V. Brunelli, M. Cappa, P. Loli, P. Beck-Peccoz, and A. Spada Growth Hormone-Releasing Hormone Resistance in Pseudohypoparathyroidism Type Ia: New Evidence for Imprinting of the Gs{alpha} Gene J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4070 - 4074. [Abstract] [Full Text] [PDF]

				M. C. B. V. Fragoso, S. Domenice, A. C. Latronico, R. M. Martin, M. A. A. Pereira, M. C. N. Zerbini, A. M. Lucon, and B. B. Mendonca Cushing's Syndrome Secondary to Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia due to Activating Mutations of GNAS1 Gene J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2147 - 2151. [Abstract] [Full Text] [PDF]

				J Singh, N Moghal, S H S Pearce, and T Cheetham The investigation of hypocalcaemia and rickets Arch. Dis. Child., May 1, 2003; 88(5): 403 - 407. [Abstract] [Full Text] [PDF]

				A. Lania, M. Filopanti, S. Corbetta, M. Losa, E. Ballare, P. Beck-Peccoz, and A. Spada Effects of Hypothalamic Neuropeptides on Extracellular Signal-Regulated Kinase (ERK1 and ERK2) Cascade in Human Tumoral Pituitary Cells J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1692 - 1696. [Abstract] [Full Text] [PDF]

				S. F. Steinberg Focus on "Targeted expression of activated Q227L Galpha s in vivo" Am J Physiol Cell Physiol, August 1, 2002; 283(2): C383 - C385. [Full Text] [PDF]

				Genetically Modified Animals in Endocrinology Endocr. Rev., April 1, 2002; 23(2): 276 - 278. [Full Text] [PDF]