Primary Generalized Glucocorticoid Resistance Follow-up

  • Author: Evangelia Charmandari, MD, MRCP, MSc; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Jul 27, 2010
 

Further Inpatient Care

  • Regular follow-up appointments in which body weight and blood pressure are monitored are necessary.
  • Clinical and biochemical indices of glucocorticoid action should be monitored as well.
 
Contributor Information and Disclosures
Author

Evangelia Charmandari, MD, MRCP, MSc  Pediatric and Adolescent Endocrinologist, Senior Investigator, Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, Greece

Evangelia Charmandari, MD, MRCP, MSc is a member of the following medical societies: British Medical Association and Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Tomoshige Kino, MD, PhD  Staff Scientist, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health

Tomoshige Kino, MD, PhD is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Thomas A Wilson, MD  Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD  Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Literary work of this article was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland), the EU-European Social Fund, and the Greek Ministry of Development-General Secretariat of Research and Technology (Athens, Greece).

References

  1. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. Winter 1984;5(1):25-44. [Medline].

  2. Clark JK, Schrader WT, O'Malley BW. Mechanism of steroid hormones. In: JD Wilson, DW Foster, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders Co; 1992:35-90.

  3. Simpson HW, McArdle CS, Griffiths K, Turkes A, Beastall GH. Progesterone resistance in women who have had breast cancer. Br J Obstet Gynaecol. Mar 1998;105(3):345-51. [Medline].

  4. Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. Jan 2002;16(1):61-71. [Medline].

  5. Chrousos GP, Vingerhoeds A, Brandon D, Eil C, Pugeat M, DeVroede M. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest. Jun 1982;69(6):1261-9. [Medline].

  6. Chrousos GP, Detera-Wadleigh SD, Karl M. Syndromes of glucocorticoid resistance. Ann Intern Med. Dec 1 1993;119(11):1113-24. [Medline].

  7. Cole TJ, Blendy JA, Monaghan AP, et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. Jul 1 1995;9(13):1608-21. [Medline].

  8. Zennaro MC. Mineralocorticoid resistance. Steroids. Apr 1996;61(4):189-92. [Medline].

  9. McPhaul MJ, Marcelli M, Zoppi S, Griffin JE, Wilson JD. Genetic basis of endocrine disease. 4. The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J Clin Endocrinol Metab. Jan 1993;76(1):17-23. [Medline].

  10. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. Oct 20 1994;331(16):1056-61. [Medline].

  11. Hewison M, Rut AR, Kristjansson K, et al. Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene. Clin Endocrinol (Oxf). Dec 1993;39(6):663-70. [Medline].

  12. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev. Jun 1993;14(3):348-99. [Medline].

  13. Carson-Jurica MA, Schrader WT, O'Malley BW. Steroid receptor family: structure and functions. Endocr Rev. May 1990;11(2):201-20. [Medline].

  14. Picard D, Yamamoto KR. Two signals mediate hormone-dependent nuclear localization of the glucocorticoid receptor. EMBO J. Nov 1987;6(11):3333-40. [Medline].

  15. Hollenberg SM, Evans RM. Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell. Dec 2 1988;55(5):899-906. [Medline].

  16. Dalman FC, Scherrer LC, Taylor LP, Akil H, Pratt WB. Localization of the 90-kDa heat shock protein-binding site within the hormone-binding domain of the glucocorticoid receptor by peptide competition. J Biol Chem. Feb 25 1991;266(6):3482-90. [Medline].

  17. Hollenberg SM, Weinberger C, Ong ES, et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. Dec 19-1986 Jan 1 1985;318(6047):635-41. [Medline].

  18. Pratt WB. The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor. J Biol Chem. Oct 15 1993;268(29):21455-8. [Medline].

  19. Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev. Jun 1996;17(3):245-61. [Medline].

  20. Terry LJ, Shows EB, Wente SR. Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science. Nov 30 2007;318(5855):1412-6. [Medline].

  21. Schaaf MJ, Cidlowski JA. Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol. Dec 2002;83(1-5):37-48. [Medline].

  22. Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. Sep 21 1990;62(6):1189-204. [Medline].

  23. Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS Jr. Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol. Feb 1995;15(2):943-53. [Medline].

  24. Kino T, Chrousos GP. Tissue-specific glucocorticoid resistance-hypersensitivity syndromes: multifactorial states of clinical importance. J Allergy Clin Immunol. Apr 2002;109(4):609-13. [Medline].

  25. Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci STKE. Oct 4 2005;2005(304):pe48. [Medline].

  26. Liu J, DeFranco DB. Protracted nuclear export of glucocorticoid receptor limits its turnover and does not require the exportin 1/CRM1-directed nuclear export pathway. Mol Endocrinol. Jan 2000;14(1):40-51. [Medline].

  27. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. Jun 1999;20(3):321-44. [Medline].

  28. McKenna NJ, O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. Feb 22 2002;108(4):465-74. [Medline].

  29. McKenna NJ, Xu J, Nawaz Z, Tsai SY, Tsai MJ, O'Malley BW. Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol. Apr-Jun 1999;69(1-6):3-12. [Medline].

  30. Auboeuf D, Honig A, Berget SM, O'Malley BW. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science. Oct 11 2002;298(5592):416-9. [Medline].

  31. Hittelman AB, Burakov D, Iniguez-Lluhi JA, Freedman LP, Garabedian MJ. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. EMBO J. Oct 1 1999;18(19):5380-8. [Medline].

  32. Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. Jun 12 1997;387(6634):733-6. [Medline].

  33. Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes. J Endocrinol. Jun 2001;169(3):437-45. [Medline].

  34. Chrousos GP. Hormone Resistance and Hypersensitivity States. In: Chrousos GP, Olefsky JM, Samols E, eds. Modern Endocrinology Series. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002:542.

  35. Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes. J Steroid Biochem Mol Biol. Jun 2003;85(2-5):457-67. [Medline].

  36. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab. May 2008;93(5):1563-72. [Medline].

  37. de Castro M, Elliot S, Kino T, et al. The non-ligand binding beta-isoform of the human glucocorticoid receptor (hGR beta): tissue levels, mechanism of action, and potential physiologic role. Mol Med. Sep 1996;2(5):597-607. [Medline].

  38. Oakley RH, Webster JC, Sar M, Parker CR Jr, Cidlowski JA. Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor. Endocrinology. Nov 1997;138(11):5028-38. [Medline].

  39. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. Sep 24 1999;274(39):27857-66. [Medline].

  40. Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. Nov 3 1997;186(9):1567-74. [Medline].

  41. Shahidi H, Vottero A, Stratakis CA, et al. Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun. Jan 27 1999;254(3):559-65. [Medline].

  42. Longui CA, Vottero A, Adamson PC, et al. Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia. Horm Metab Res. Oct 2000;32(10):401-6. [Medline].

  43. Hauk PJ, Goleva E, Strickland I, et al. Increased glucocorticoid receptor Beta expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype. Am J Respir Cell Mol Biol. Sep 2002;27(3):361-7. [Medline].

  44. Hauk PJ, Hamid QA, Chrousos GP, Leung DY. Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol. Apr 2000;105(4):782-7. [Medline].

  45. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. May 18 1995;332(20):1351-62. [Medline].

  46. Vingerhoeds AC, Thijssen JH, Schwarz F. Spontaneous hypercortisolism without Cushing's syndrome. J Clin Endocrinol Metab. Nov 1976;43(5):1128-33. [Medline].

  47. Kino T, Vottero A, Charmandari E, Chrousos GP. Familial/sporadic glucocorticoid resistance syndrome and hypertension. Ann N Y Acad Sci. Sep 2002;970:101-11. [Medline].

  48. Charmandari E, Kino T, Chrousos GP. Familial/sporadic glucocorticoid resistance: clinical phenotype and molecular mechanisms. Ann N Y Acad Sci. Jun 2004;1024:168-81. [Medline].

  49. Karl M, Lamberts SW, Koper JW, Katz DA, Huizenga NE, Kino T. Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians. Jul 1996;108(4):296-307. [Medline].

  50. Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. Feb 1991;87(2):680-6. [Medline].

  51. Karl M, Lamberts SW, Detera-Wadleigh SD, Encio IJ, Stratakis CA, Hurley DM. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab. Mar 1993;76(3):683-9. [Medline].

  52. Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. May 1993;91(5):1918-25. [Medline].

  53. Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. Nov 2001;86(11):5600-8. [Medline].

  54. Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). Sep 2001;55(3):363-71. [Medline].

  55. Mendonca BB, Leite MV, de Castro M, Kino T, Elias LL, Bachega TA. Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. J Clin Endocrinol Metab. Apr 2002;87(4):1805-9. [Medline].

  56. Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. Jun 2002;87(6):2658-67. [Medline].

  57. Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharyya N, Chrousos GP. Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype. J Clin Endocrinol Metab. Apr 2004;89(4):1939-49. [Medline].

  58. Charmandari E, Raji A, Kino T, et al. A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity. J Clin Endocrinol Metab. Jun 2005;90(6):3696-705. [Medline].

  59. Charmandari E, Kino T, Ichijo T, Zachman K, Alatsatianos A, Chrousos GP. Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRalphaR477H and hGRalphaG679S associated with generalized glucocorticoid resistance. J Clin Endocrinol Metab. Apr 2006;91(4):1535-43. [Medline].

  60. Charmandari E, Kino T, Ichijo T, Jubiz W, Mejia L, Zachman K. A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. J Clin Endocrinol Metab. Oct 2007;92(10):3986-90. [Medline].

  61. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259-84. [Medline].

  62. Kino T, Liou SH, Charmandari E, Chrousos GP. Glucocorticoid receptor mutants demonstrate increased motility inside the nucleus of living cells: time of fluorescence recovery after photobleaching (FRAP) is an integrated measure of receptor function. Mol Med. Jul-Dec 2004;10(7-12):80-8. [Medline].

  63. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell. Jul 12 2002;110(1):93-105. [Medline].

  64. Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem. Jun 20 2003;278(25):22748-54. [Medline].

  65. Zhang S. Role of the C terminus of the glucocorticoid receptor in hormone binding and agonist/antagonist discrimination. Mol Endocrinol. 1996;10(1):24-34.

  66. Savory JG, Hsu B, Laquian IR, Giffin W, Reich T, Hache RJ. Discrimination between NL1- and NL2-mediated nuclear localization of the glucocorticoid receptor. Mol Cell Biol. Feb 1999;19(2):1025-37. [Medline].

  67. Qi M, Hamilton BJ, DeFranco D. v-mos oncoproteins affect the nuclear retention and reutilization of glucocorticoid receptors. Mol Endocrinol. Aug 1989;3(8):1279-88. [Medline].

  68. Wikstrom AC, Bakke O, Okret S, Bronnegard M, Gustafsson JA. Intracellular localization of the glucocorticoid receptor: evidence for cytoplasmic and nuclear localization. Endocrinology. Apr 1987;120(4):1232-42. [Medline].

  69. Holaska JM, Black BE, Rastinejad F, Paschal BM. Ca2+-dependent nuclear export mediated by calreticulin. Mol Cell Biol. Sep 2002;22(17):6286-97. [Medline].

  70. Black BE, Holaska JM, Rastinejad F, Paschal BM. DNA binding domains in diverse nuclear receptors function as nuclear export signals. Curr Biol. Nov 13 2001;11(22):1749-58. [Medline].

  71. Dahlman-Wright K, Wright A, Gustafsson JA, Carlstedt-Duke J. Interaction of the glucocorticoid receptor DNA-binding domain with DNA as a dimer is mediated by a short segment of five amino acids. J Biol Chem. Feb 15 1991;266(5):3107-12. [Medline].

  72. Umesono K, Evans RM. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell. Jun 30 1989;57(7):1139-46. [Medline].

  73. Liden J, Delaunay F, Rafter I, Gustafsson J, Okret S. A new function for the C-terminal zinc finger of the glucocorticoid receptor. Repression of RelA transactivation. J Biol Chem. Aug 22 1997;272(34):21467-72. [Medline].

  74. Reichardt HM, Kaestner KH, Wessely O, Gass P, Schmid W, Schutz G. Analysis of glucocorticoid signalling by gene targeting. J Steroid Biochem Mol Biol. Apr 1998;65(1-6):111-5. [Medline].

  75. Tao Y, Williams-Skipp C, Scheinman RI. Mapping of glucocorticoid receptor DNA binding domain surfaces contributing to transrepression of NF-kappa B and induction of apoptosis. J Biol Chem. Jan 26 2001;276(4):2329-32. [Medline].

  76. Ding XF, Anderson CM, Ma H, Hong H, Uht RM, Kushner PJ. Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol. Feb 1998;12(2):302-13. [Medline].

  77. Hong H, Kohli K, Garabedian MJ, Stallcup MR. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol. May 1997;17(5):2735-44. [Medline].

  78. Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci U S A. May 14 1996;93(10):4948-52. [Medline].

  79. Danielian PS, White R, Lees JA, Parker MG. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. Mar 1992;11(3):1025-33. [Medline].

  80. Steinmetz AC, Renaud JP, Moras D. Binding of ligands and activation of transcription by nuclear receptors. Annu Rev Biophys Biomol Struct. 2001;30:329-59. [Medline].

  81. Darimont BD, Wagner RL, Apriletti JW, Stallcup MR, Kushner PJ, Baxter JD. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. Nov 1 1998;12(21):3343-56. [Medline].

  82. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. Oct 2004;25(5):831-66. [Medline].

  83. Wilson JD, Griffin JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev. Oct 1993;14(5):577-93. [Medline].

  84. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. May 13 2006;367(9522):1605-17. [Medline].

  85. Huizenga NA, de Lange P, Koper JW, de Herder WW, Abs R, Kasteren JH. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene. J Clin Endocrinol Metab. May 2000;85(5):2076-81. [Medline].

 
Previous
Next
 
Schematic representation of the structure of the human glucocorticoid receptor (hGR) gene. Alternative splicing of the primary transcript gives rise to the 2 mRNA and protein isoforms, hGRα and hGRβ.
Functional domains of human glucocorticoid receptor (hGR)α. The functional domains and subdomains are indicated beneath the linearized protein structures. AF = Activation function; DBD = DNA-binding domain; LBD = Ligand-binding domain; NLS = Nuclear localization signal.
Nucleocytoplasmic shuttling of the glucocorticoid receptor. Upon binding to the ligand, the activated human glucocorticoid receptor (hGR)α dissociates from heat shock proteins (hsps) and translocates into the nucleus, where it homodimerizes and binds to glucocorticoid response elements (GREs) in the promoter region of target genes. TF = Transcription factor; TFRE = Transcription factor response element.
Schematic representation of the interaction of activation function (AF)-1 and AF-2 of human glucocorticoid receptor (hGR)α with coactivators. DRIP/TRAP = Vitamin D receptor-interacting protein/thyroid hormone receptor-associated protein; GREs = Glucocorticoid response elements; SWI/SNF = Switching/sucrose nonfermenting.
Location of the known mutations of the glucocorticoid receptor (hGR) gene (upper panel) and protein (lower panel). DBD = DNA-binding domain; NTD = Amino terminal domain; LBD = Ligand-binding domain.
Crystal structure of the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR)α. Stereotactic conformation of the agonist (left) and antagonist (right) form of the LBD of hGRα. The yellow arrows indicate the position of helix 12, which is critical for the formation of activation function (AF)-2 surface that allows interaction with activators.
Location of the known mutations of human glucocorticoid receptor(hGR)α in the agonist (upper panel) and antagonist (lower panel) form of the LBD of hGRα. Helices are indicated in red and are underlined, whereas β-sheets are indicated in green. Two mutations (I559 and V571A) are located within H5, whereas 4 mutations (V729I, F737L, I747M, and L773P) are located within or close to helices 11 and 12. The ligand-binding pocket is formed by helices 3, 5, 11, and 12. Upon ligand-binding, the receptor undergoes major conformational changes that alter the position of helix 11 and helix 12 and generate an interaction surface that allows coactivators to bind to the LBD through their LXXLL motifs. Helix 12 plays a critical role in the formation of both the ligand-binding pocket and the activation function (AF)-2 surface that facilitates interaction with coactivators. The fact that most hGRα mutations are clustered around helix 5, helix 11, and helix 12 indicates that these helices play an important role in glucocorticoid signal transduction.
Alterations in the hypothalamic-pituitary-adrenal (HPA) axis in primary generalized glucocorticoid resistance. The impaired glucocorticoid feedback inhibition at the hypothalamic and anterior pituitary levels results in increased secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH), adrenal hyperplasia, and increased secretion of adrenal steroids with mineralocorticoid and/or androgenic activity. AVP = Arginine vasopressin; DOC = Deoxycorticosterone.
Table. Mutations of the Human Glucocorticoid Receptor Gene Causing Primary Generalized Glucocorticoid Resistance
Mutation Position Molecular Mechanisms Genotype Phenotype
cDNAAmino Acid
1922 (A → T)641 (D → V)Transactivation ↓



Affinity for ligand ↓ (x3)



Nuclear translocation: 22 min



Abnormal interaction with GRIP1



HomozygousHypertension, hypokalemic alkalosis
4 bp deletion in exon-intron 6hGRα number: 50% of control,



inactivation of the affected allele



HeterozygousHirsutism,



male-pattern hair loss, menstrual irregularities



2185 (G → A)729 (V → I)Transactivation ↓,



affinity for ligand ↓ (x2),



nuclear translocation: 120 min,



abnormal interaction with GRIP1



HomozygousPrecocious puberty,



hyperandrogenism



1676 (T → A)559 (I → N)Transactivation ↓, decrease in hGR binding sites,



transdominance (+), nuclear translocation: 180 min, abnormal interaction with GRIP1



HeterozygousHypertension,



oligospermia, infertility



1430 (G → A)477 (R → H)Transactivation ↓, no DNA binding,



nuclear translocation: 20 min



HeterozygousHirsutism,



fatigue, hypertension



2035 (G → A)679 (G → S)Transactivation ↓, affinity for ligand ↓ (x2),



nuclear translocation: 30 min, abnormal interaction with GRIP1



HeterozygousHirsutism, fatigue, hypertension
1712 (T → C)571 (V → A)Transactivation ↓, affinity for ligand ↓ (x6),



nuclear translocation: 25 min, abnormal interaction with GRIP1



HomozygousAmbiguous genitalia, hypertension,



hypokalemia, hyperandrogenism



2241 (T → G)747 (I → M)Transactivation ↓, transdominance (+), affinity for ligand ↓ (x2), nuclear translocation ↓,



abnormal interaction with GRIP1



HeterozygousCystic acne, hirsutism, oligo-amenorrhea
2318 (T → C)773 (L → P)Transactivation ↓, transdominance (+), affinity for ligand ↓ (x2.6),



nuclear translocation: 30 min, abnormal interaction with GRIP1



HeterozygousFatigue, anxiety, acne, hirsutism, hypertension
2209 (T → C)737 (F → L)Transactivation ↓, transdominance (time-dependent) (+), affinity for ligand ↓ (x1.5), nuclear translocation: 180 min, abnormal interaction with GRIP1HeterozygousHypertension, hypokalemia
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.