Mutations in the Gs alpha gene causing hormone resistance.
G-protein-coupled receptors (GPCRs) and G proteins mediate the effects of a number of hormones of relevance to endocrinology. Genes encoding these molecules may be targets of loss- or gain-of-function mutations, resulting in endocrine disorders. The only mutational change of G proteins so far unequivocally associated with endocrine disorders occurs in the Gsalpha gene (GNAS1, guanine nucleotide binding protein alpha stimulating activity polypeptide 1), which activates cyclic AMP (cAMP)-dependent pathways. Heterozygous loss-of-function mutations of GNAS1 in the active maternal allele cause resistance to hormones acting through Gsalpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of endocrine cells recognizing cAMP as mitogen. This review will focus on inactivating mutations leading to hormone resistance syndromes, i.e., pseudohypoparathyroidism types Ia and Ib.
Mantovani
Giovanna
G
Endocrine Unit, Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore, Policlinico, Mangiagalli e Regina Elena IRCCS, Via F. Sforza, 35, 20122 Milan, Italy. giovanna.mantovani@unimi.it
Spada
Anna
A
D002864:Chromogranins; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D009154:Mutation; D010281:Parathyroid Hormone / Q000494:pharmacology; D011547:Pseudohypoparathyroidism / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics
D002864:Chromogranins; D010281:Parathyroid Hormone; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs