G proteins and
G-protein-coupled receptors (GPCRs) mediate the effects of a number of
hormones. Genes that encode these molecules are subject to loss-of function or gain-of-function mutations that result in endocrine disorders. Loss-of-function mutations prevent signaling in response to the corresponding agonist and cause resistance to
hormone actions, which mimics
hormone deficiency. Gain-of-function mutations lead to constitutive, agonist-independent activation of signaling, which mimics
hormone excess. Disease-causing mutations of GPCRs have been identified in patients with various disorders of the pituitary-thyroid, pituitary-gonadal and pituitary-adrenal axes, and in those with abnormalities in food intake, growth, water balance and
mineral-ion turnover. The only mutational changes in
G proteins unequivocally associated with endocrine disorders occur in GNAS (
guanine nucleotide-
binding protein G-stimulatory subunit alpha, or
G(s)alpha). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to
hormones that act through
G(s)alpha-coupled GPCRs, whereas somatic gain-of-function mutations cause proliferation of endocrine cells that recognize
cyclic AMP as a
mitogen. The study of mutations in
G proteins and GPCRs has already had major implications for understanding the molecular basis of rare
endocrine diseases, as well as susceptibility to multifactorial disorders that are associated with polymorphisms in these genes.