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Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases

Abstract

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 α, or Gsα). Heterozygous loss-of-function mutations of GNAS in the active, maternal allele cause resistance to hormones that act through Gsα-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.

Key Points

  • Genes that encode G-protein-coupled receptors (GPCRs) and G proteins can have loss-of-function or gain-of-function mutations, which result in endocrine disorders

  • Loss-of-function mutations in GPCRs and G proteins prevent signaling in response to the corresponding agonist, and cause resistance to hormone action, which mimics hormone deficiency

  • Gain-of-function mutations in GPCRs and G proteins lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess

  • The diseases caused by genetic defects in GPCRs and G proteins are rare, and diagnosis requires careful clinical and biochemical work-up as well as close collaboration between clinical and molecular endocrinologists

  • The study of the phenotypic consequences of mutations in GPCRs and G proteins has already had major implications for understanding structure–function relationships of these molecules, even if the implications for treatment of patients who carry such mutations are limited, at present

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Figure 1: Schematic representation of GPCRs and G proteins

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, and Ricerca Corrente Funds of Fondazione Policlinico Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

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Lania, A., Mantovani, G. & Spada, A. Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nat Rev Endocrinol 2, 681–693 (2006). https://doi.org/10.1038/ncpendmet0324

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