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
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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
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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
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Gain-of-function mutations in GPCRs and G proteins lead to constitutive, agonist-independent activation of signaling, which mimics hormone excess
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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
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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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References
Fredriksson R and Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67: 1414–1425
Hollmann MW et al. (2005) Receptors, G proteins and their interactions. Anesthesiology 103: 1066–1078
Perez DM and Karnik SS (2005) Multiple signaling states of G-protein-coupled receptors. Pharmacol Rev 57: 147–161
Spiegel AM and Weinstein LS (2004) Inherited diseases involving G proteins and G protein-coupled receptors. Annu Rev Med 55: 27–39
Brothers SP et al. (2004) Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Mol Endocrinol 18: 1787–1797
Collu R et al. (1997) A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 82: 1561–1565
Abramowicz MJ et al. (1997) Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 99: 3018–3024
Sunthornthepvarakul T et al. (1995) Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 332: 155–160
Davies TF et al. (2005) Thyrotropin receptor-associated diseases: from adenomas to Graves disease. J Clin Invest 115: 1972–1983
Parma J et al. (1993) Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365: 649–651
Krohn K et al. (2005) Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 26: 504–524
Fuhrer et al. (1997) Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 82: 4234–4238
Rodien P et al. (1998) Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 339: 1823–1826
de Roux N et al. (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 100: 10972–10976
de Roux N et al. (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 337: 1597–1602
Karges B et al. (2003) Clinical and molecular genetics of the human GnRH receptor. Hum Reprod Update 9: 523–530
Chanson P et al. (1998) Absence of activating mutations in the GnRH receptor gene in human pituitary gonadotroph adenomas. Eur J Endocrinol 139: 157–160
Themmen APN (2005) An update of the pathophysiology of human gonadotropin subunit and receptor gene mutations and polymorphisms. Reproduction 130: 263–274
Berthezene F et al. (1976) Leydig-cell agenesis: a cause of male pseudohermaphroditism. N Engl J Med 295: 969–972
Shenker A et al. (1993) A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365: 652–654
Liu G et al. (1999) Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med 341: 1731–1736
Aittomaki K et al. (1995) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82: 959–968
Gromoll J et al. (1996) An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 81: 1367–1370
Kaiser UB (2003) The pathogenesis of the ovarian hyperstimulation syndrome. N Engl J Med 349: 729–732
Clark AJ et al. (1993) Familial glucocorticoid deficiency associated with a point mutation in the adrenocorticotropin receptor. Lancet 341: 461–462
Clark AJ et al. (2005) Inherited ACTH insensitivity illuminates the mechanisms of ACTH action. Trends Endocrinol Metab 16: 451–457
Lacroix A et al. (1992) Gastric inhibitory polypeptide-dependent cortisol hypersecretion: a new cause of Cushing's syndrome. N Engl J Med 327: 974–980
Lacroix A et al. (2001) Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev 22: 75–110
Yeo GS et al. (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20: 111–112
Farooqi IS and O'Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56: 443–458
Govaerts C et al. (2005) Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function. Peptides 26: 1909–1919
Maheshwari HG et al. (1998) Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab 83: 4065–4074
Alba M and Salvatori R (2004) Familial growth hormone deficiency and mutations in the GHRH receptor gene. Vitam Horm 69: 209–220
Lee EJ et al. (2001) Absence of constitutively activating mutations in the GHRH receptor in GH-producing pituitary tumors. J Clin Endocrinol Metab 86: 3989–3995
Pantel J et al. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116: 760–768
Rosenthal W et al. (1992) Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 359: 233–235
Knoers NV and Deen PM (2001) Molecular and cellular defects in nephrogenic diabetes insipidus. Pediatr Nephrol 16: 1146–1152
van Lieburg AF et al. (1995) Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. Hum Genet 96: 70–78
Nomura Y et al. (1997) Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 82: 3434–3437
Ala Y et al. (1998) Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 9: 1861–1872
Feldman BJ et al. (2005) Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 352: 1884–1889
Pollak MR et al. (1993) Mutations in the human Ca2 sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297–1303
Thakker RV (2004) Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium 35: 275–282
Hendy GN et al. (2000) Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 16: 281–296
Baron J et al. (1996) Mutations in the Ca2-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet 5: 601–606
Okazaki R et al. (1999) A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia. J Clin Endocrinol Metab 84: 363–366
Lovlie K et al. (1996) The Ca2 sensing receptor gene (PCAR1) mutation T151M in isolated autosomal dominant hypoparathyroidism. Hum Genet 98: 129–133
Lienhardt A et al. (2001) Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 86: 5313–5323
Jobert A-S et al. (1998) Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 102: 34–40
Schipani E et al. (1996) Constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med 335: 708–714
Lyons et al. (1990) Two G protein oncogenes in human endocrine tumors. Science 249: 655–659
Wettschureck N and Offermanns S (2005) Mammalian G proteins and their cell type specific functions. Physiol Rev 85: 1159–1204
Dryja TP et al. (1996) Missense mutation in the gene encoding the α subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nat Genet 13: 358–360
Weinstein LS et al. (2004) Minireview: GNAS: normal and abnormal functions. Endocrinology 145: 5459–5464
Weinstein LS et al. (1990) Mutations of the Gsα-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 87: 8287–8290
Weinstein LS et al. (2001) Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr Rev 22: 675–705
Mantovani G et al. (2003) Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gsα gene. J Clin Endocrinol Metab 88: 4070–4074
Germain-Lee EL et al. (2003) Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 88: 4059–4069
Mantovani G et al. (2002) The Gsα gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 87: 4736–4740
Hayward BE et al. (2001) Imprinting of the Gsα gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107: R31–R36
Shore EM et al. (2002) Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 346: 99–106
Iiri T et al. (1994) Rapid GDP release from Gsα in patients with gain and loss of endocrine function. Nature 371: 164–168
Juppner H et al. (1998) The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA 95: 11798–11803
Linglart A et al. (2005) A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 76: 804–814
Bastepe M et al. (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet 37: 25–27
Liu J et al. (2005) Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum Mol Genet 14: 95–102
Landis CA et al. (1989) GTPase inhibiting mutations activate the α chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340: 692–696
Lania A et al. (2001) G-protein mutations in endocrine diseases. Eur J Endocrinol 145: 543–559
Roman R et al. (2004) Activating GNAS1 gene mutations in patients with premature thelarche. J Pediatr 145: 218–222
Kalfa N et al. (2006) Activating mutations of the stimulatory G protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab 91: 1842–1847
Spada A et al. (1990) Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 71: 1421–1426
Lania A et al. (1998) Constitutively active Gsα is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas. J Clin Endocrinol Metab 83: 1624–1628
Ballare E et al. (1998) Activating mutations of the Gsα gene are associated with low levels of Gsα protein in growth hormone-secreting tumors. J Clin Endocrinol Metab 83: 4386–4390
Weinstein LS et al. (1991) Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med 325: 1688–1695
Mantovani G et al. (2004) A parental origin of Gsα mutations in the McCune–Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 89: 3007–3009
Shenker A et al. (1995) Osteoblastic cells derived from isolated lesions of fibrous dysplasia contain activating somatic mutations of the Gsα gene. Hum Mol Genet 4: 1675–1676
Thompson MD et al. (2005) The G protein-coupled receptors: pharmacogenetics and disease. Crit Rev Clin Lab Sci 42: 311–392
Gromoll J and Simoni E (2005) Genetic complexity of FSH receptor function. Trends Endocrinol Metab 8: 368–373
Jia H et al. (1999) Association of the Gsα gene with essential hypertension and response to β-blockade. Hypertension 34: 8–14
Siffert W (2005) G protein polymorphisms in hypertension, atherosclerosis, and diabetes. Annu Rev Med 56: 17–28
Siffert W et al. (1998) Association of a human G-protein β3 subunit variant with hypertension. Nat Genet 18: 45–48
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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DOI: https://doi.org/10.1038/ncpendmet0324
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