This review summarizes the role of the molecular pathogenesis of Gsalpha protein gene in endocrine disease. G proteins transmit the cellular signal of 7 transmembrane receptors (7TM). Agonists as light photons, odorants and hormones (LH, FSH, TSH, PTH, etc) can activate the system. The effector of Gsalpha protein is adenyl-cyclase, which induces the formation of cAMP. The receptors that activate Gsalpha protein dissociates GDT into GTP, while the intrinsic GTPase activity hydrolyses GTP, keeping Gsalpha protein in its inactive state, bound to GDP. Mutations in the GNAS1 gene, which codifies the Gsalpha protein, alter highly conserved sites (Arg201 and Gln227) that are critical for GTPase activity, leading to the constitutive activation of cell signaling. Such mutations are found in rare endocrine tumors, bone fibrodysplasia and McCune Albright syndrome. Conversely, inactivating mutations can lead to Albright hereditary osteodystrophy or pseudohypoparathyroidism type Ia, when transmitted by the paternal or maternal alleles, respectively. In knockout female mice the Gnas gene exhibits the phenomenon of tissue-specific imprinting. In pituitary tumors the GNAS1 gene also undergoes imprinting, when expressed preferably by the maternal allele. In pseudohypoparathyroidism type Ib, a defect of imprinting in the promoter region of exon 1A of GNAS1 gene appears to justify the isolated renal resistance to PTH. These examples illustrate how defects in Gsalpha protein can be responsible for the molecular pathogenesis of different endocrine disorders.
Gsalpha protein; GNAS1 gene; Mutations; Imprinting
