GNAS generates multiple gene products through the use of alternative promoters and first exons that splice onto a common exon. The most downstream alternative promotergenerates transcripts encoding the ubiquitously expressed G protein α-subunit Gsα that couples many receptors for hormones, neurotransmitters and other extracellular signals to adenylyl cyclase. Gsα is required for receptor-stimulated cAMP production and most of its downstream effects are mediated via cAMP, which in turn activates signaling molecules such as protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). PKA is a serine/threonine kinase which acutely activates many metabolic processes such as lipolysis, gluconeogenesis, and glycogenolysis through direct phosphorylation of enzymes and other factors involved in intermediary metabolism. In addition PKA has more chronic effects on gene expression by phosphorylation of transcription factors such as the cAMP response element binding protein (CREB).
GNAS mutations result in various non-cancerous diseases: pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone. Genetic alterations in GNAS may also be the cause of a subset of growth hormone secreting pituitary tumors (somatotrophinoma).
Somatic GNAS point mutations (exclusively “substitution missense”) have been observed in tumors of pituitary (about 25% of cases), ovary and testis (about 15%) parathyroid, kidney, thyroid, adrenal gland, large intestine, autonomic ganglia and lung.
There are two mutation hot spots corresponding to amino acids 201 and 227.
Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. Mantovani G, Bondioni S, Lania AG, Corbetta S, de Sanctis L, Cappa M, Di Battista E, Chanson P, Beck-Peccoz P, Spada A. J Clin Endocrinol Metab. 2004 Jun;89(6):3007-9.
The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. Wilson CH, McIntyre RE, Arends MJ, Adams DJ. Oncogene. 2010 Aug 12;29(32):4567-75.