Monday 29 September 2003
Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins.
The activity of hormone-sensitive adenylate cyclase is regulated by at least 2 G proteins, 1 stimulatory (Gs) and 1 inhibitory (Gi) (MIM.139310). A third G protein, Go (MIM.139311), is abundant in brain.
Each G protein is a heterotrimer composed of an alpha, beta, and gamma subunit. The GNAS1 gene encodes the alpha subunit of the G stimulatory protein Gs.
Neuroendocrine secretory protein-55 (NESP-55), the latest addition to the chromogranin family, is a product of a genomically imprinted gene transcribed exclusively from the maternal allele.
Expression in tumors
pancreatic endocrine tumors
neuroblastomas (50%) (#12771991#)
Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and, more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues.
heterozygous deactivating GNAS1 mutations in Albright hereditary osteodystrophy (AHO)
- Maternally derived mutations are usually associated with resistance to parathyroid hormone termed "pseudohypoparathyroidism type Ia."
- Paternally derived mutations are associated with AHO but usually normal hormone responsiveness, known as "pseudo-pseudohypoparathyroidism."
mutations in fibrous dysplasia
liposclerosing myxofibrous tumor (#14652823#)
mutations of GNAS1
- Albright hereditary osteodystrophy
- pseudohypoparathyroidism type Ia (PHP Ia) vpseudopseudohypoparathyroidism (PPHP)
- pituitary tumors
- fibrous dysplasia
- liposclerosing myxofibrous tumor
- unilateral macro-orchidism without sexual precocity in McCune-Albright syndrome (#17101633#, #16462147#)
- The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. (#20531296#)
- Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and, more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues.
- GNAS R201C expression was associated with elevated expression of Wnt and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway target genes, increased phosphorylation of ERK1/2 MAPK and increased immunostaining for the proliferation marker Ki67. (#20531296#)
- The effects of GNAS-R201C on the Wnt pathway were additive to the inactivation of APC. (#20531296#)
- Activating mutations of GNAS cooperate with inactivation of APC and are likely to contribute to colorectal tumourigenesis. (#20531296#)
The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. (#20531296#)
Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune-Albright syndrome. Rey RA, Venara M, Coutant R, Trabut JB, Rouleau S, Lahlou N, Sultan C, Limal JM, Picard JY, Lumbroso S. Hum Mol Genet. 2006 Dec 15;15(24):3538-43.PMID: #17101633#
McCune-Albright syndrome in a boy may present with a monolateral macroorchidism as an early and isolated clinical manifestation. Arrigo T, Pirazzoli P, De Sanctis L, Leone O, Wasniewska M, Messina MF, De Luca F. Horm Res. 2006;65(3):114-9. PMID: #16462147#
Srivastava A, Padilla O, Fischer-Colbrie R, Tischler AS, Dayal Y. Neuroendocrine secretory protein-55 (NESP-55) expression discriminates pancreatic endocrine tumors and pheochromocytomas from gastrointestinal and pulmonary carcinoids. Am J Surg Pathol. 2004 Oct;28(10):1371-8. PMID: #15371954#