Biopolym. Cell. 2012; 28(5):338-351.
http://dx.doi.org/10.7124/bc.000061
Reviews
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications
1Orlovsky M. A.
  1. O. O. Bogomoletz Institute of Physiology, NAS of Ukraine
    Akademika Bogomoltsa Str., 4, Kyiv, Ukraine, 01004

Abstract

Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.
Keywords: glucocorticoid receptors, allelic polymorphism, SNP, NR3C1, GR, stress-induced pathology
Full text: (PDF, in English) (PDF, in Russian)

References

[1] Bronnegard M., Stierna P., Marcus C. Glucocorticoid resistant syndromes – molecular basis and clinical presentations J. Neuroendocrinol 1996 8, N 6:405–415.
[2] Bray P. J., Cotton R. G. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms Hum. Mutat 2003 21, N 6:557–568.
[3] Cao-Lei L., Leija S. C., Kumsta R., Wust S., Meyer J., Turner J. D., Muller C. P. Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions Hum. Genet 2011 129, N 5:533–543.
[4] Turner J. D., Alt S. R., Cao L., Vernocchi S., Trifonova S., Battello N., Muller C. P. Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more Biochem. Pharmacol 2010 80, N 12:1860–1868.
[5] Kumsta R., Moser D., Streit F., Koper J. W., Meyer J., Wust S. Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance Am. J. Med. Genet. B Neuropsychiatr. Genet 2009 150B, N 4:476–482.
[6] Lu N. Z., Cidlowski J. A. Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes Mol. Cell 2005 18, N 3:331–342.
[7] Touriol C., Bornes S., Bonnal S., Audigier S., Prats H., Prats A. C., Vagner S. Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons Biol. Cell 2003 95, N 3–4:169–178.
[8] de Kloet E. R., Vreugdenhil E., Oitzl M. S., Joels M. Brain corticosteroid receptor balance in health and disease Endocr. Rev 1998 19, N 3:269–301.
[9] Oakley R. H., Sar M., Cidlowski J. A. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function J. Biol. Chem 1996 271, N 16:9550– 9559.
[10] Strickland I., Kisich K., Hauk P. J., Vottero A., Chrousos G. P., Klemm D. J., Leung D. Y. High constitutive glucocorticoid receptor beta in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids J. Exp. Med 2001 193, N 5:585–593.
[11] Otto C., Reichardt H. M., Schutz G. Absence of glucocorticoid receptor-beta in mice J. Biol. Chem 1997 272, N 42:26665– 26668.
[12] Rivers C., Levy A., Hancock J., Lightman S., Norman M. Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing J. Clin. Endocrinol. Metab 1999 84, N 11:4283–4286.
[13] Ray D. W., Davis J. R., White A., Clark A. J. Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells Cancer Res 1996 56, N 14:3276– 3280.
[14] Conway-Campbell B. L., McKenna M. A., Wiles C. C., Atkinson H. C., de Kloet E. R., Lightman S. L. Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone Endocrinology 2007 148, N 11:5470–5477.
[15] Meijer O. C. Coregulator proteins and corticosteroid action in the brain J. Neuroendocrinol 2002 14, N 6:499–505.
[16] Bledsoe R. K., Montana V. G., Stanley T. B., Delves C. J., Apolito C. J., McKee D. D., Consler T. G., Parks D. J., Stewart E. L., Willson T. M., Lambert M. H., Moore J. T., Pearce K. H., Xu H. E. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition Cell 2002 110, N 1:93–105.
[17] Lightman S. L., Conway-Campbell B. L. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration Nat. Rev. Neurosci 2010 11, N 10:710–718.
[18] Meijer O. C., de Lange E. C., Breimer D. D., de Boer A. G., Workel J. O., de Kloet E. R. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice Endocrinology 1998 139, N 4:1789–1793.
[19] Kitchener P., Di Blasi F., Borrelli E., Piazza P. V. Differences between brain structures in nuclear translocation and DNA binding of the glucocorticoid receptor during stress and the circadian cycle Eur. J. Neurosci 2004 19, N 7:1837–1846.
[20] Bodwell J. E., Hu J. M., Orti E., Munck A. Hormone-induced hyperphosphorylation of specific phosphorylated sites in the mouse glucocorticoid receptor J. Steroid Biochem. Mol. Biol 1995 52, N 2:135–140.
[21] Krstic M. D., Rogatsky I., Yamamoto K. R., Garabedian M. J. Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor Mol. Cell. Biol 1997 17, N 7:3947–3954.
[22] Wang Z., Frederick J., Garabedian M. J. Deciphering the phosphorylation «code» of the glucocorticoid receptor in vivo J. Biol. Chem 2002 277, N 29:26573–26580.
[23] Itoh M., Adachi M., Yasui H., Takekawa M., Tanaka H., Imai K. Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation Mol. Endocrinol 2002 16, N 10:2382–2392.
[24] Tian S., Poukka H., Palvimo J. J., Janne O. A. Small ubiquitinrelated modifier-1 (SUMO-1) modification of the glucocorticoid receptor Biochem. J 2002 367, Pt 3:907–911.
[25] Meijsing S. H., Pufall M. A., So A. Y., Bates D. L., Chen L., Yamamoto K. R. DNA binding site sequence directs glucocorticoid receptor structure and activity Science 2009 324, N 5925:407–410.
[26] Wang X., DeFranco D. B. Alternative effects of the ubiquitinproteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP, an E3 ligase Mol. Endocrinol 2005 19, N 6:1474–1482.
[27] Wallace A. D., Cidlowski J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids J. Biol. Chem 2001 276, N 46:42714– 42721.
[28] Kinyamu H. K., Archer T. K. Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression Mol. Cell. Biol 2003 23, N 16:5867–5881.
[29] Karl M., Lamberts S. W., Detera-Wadleigh S. D., Encio I. J., Stratakis C. A., Hurley D. M., Accili D., Chrousos G. P. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene J. Clin. Endocrinol. Metab 1993 76, N 3:683–689.
[30] Mendonca B. B., Leite M. V., de Castro M., Kino T., Elias L. L., Bachega T. A., Arnhold I. J., Chrousos G. P., Latronico A. C. Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene J. Clin. Endocrinol. Metab 2002 87, N 4:1805–1809.
[31] Chung C. C., Shimmin L., Natarajan S., Hanis C. L., Boerwinkle E., Hixson J. E. Glucocorticoid receptor gene variant in the 3' untranslated region is associated with multiple measures of blood pressure J. Clin. Endocrinol. Metab 2009 94, N 1:268–276.
[32] DeRijk R. H., Schaaf M. J., Turner G., Datson N. A., Vreugdenhil E., Cidlowski J., de Kloet E. R., Emery P., Sternberg E. M., Detera-Wadleigh S. D. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis J. Rheumatol 2001 28, N 11:2383–2388.
[33] van Rossum E. F., van den Akker E. L. Glucocorticoid resistance Endocr. Dev 2011 20:127–136.
[34] Hanna C. W., Bretherick K. L., Liu C. C., Stephenson M. D., Robinson W. P. Genetic variation within the hypothalamuspituitary-ovarian axis in women with recurrent miscarriage Hum. Reprod 2010 25, N 10:2664–2671.
[35] Pietras T., Panek M., Tworek D., Oszajca K., Wujcik R., Gorski P., Kuna P., Szemraj J.The BclI single nucleotide polymorphism of the human glucocorticoid receptor gene h-GR/NR3C1 promoter in patients with bronchial asthma: pilot study Mol. Biol. Rep 2011 38, N 6:3953–3958.
[36] Kostik M. M., Klyushina A. A., Moskalenko M. V., Scheplyagina L. A., Larionova V. I. Glucocorticoid receptor gene polymorphism and juvenile idiopathic arthritis Pediatr. Rheumatol. Online J 2011 9, N 1:2.
[37] van Oosten M. J., Dolhain R. J., Koper J. W., van Rossum E. F., Emonts M., Han K. H., Wouters J. M., Hazes J. M., Lamberts S. W., Feelders R. A. Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis Arthritis Res. Ther 2010 12, N 4 R159.
[38] Vingerhoeds A. C., Thijssen J. H., Schwarz F. Spontaneous hypercortisolism without Cushing's syndrome J. Clin. Endocrinol. Metab 1976 43, N 5:1128–1133.
[39] Hurley D. M., Accili D., Stratakis C. A., Karl M., Vamvakopoulos N., Rorer E., Constantine K., Taylor S. I., Chrousos G. P. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance J. Clin. Invest 1991 87, N 2:680–686.
[40] Krett N. L., Pillay S., Moalli P. A., Greipp P. R., Rosen S. T. A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients Cancer Res 1995 55, N 13:2727–2729.
[41] de Lange P., Segeren C. M., Koper J. W., Wiemer E., Sonneveld P., Brinkmann A. O., White A., Brogan I. J., de Jong F. H., Lamberts S. W. Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells Cancer Res 2001 61, N 10:3937–3941.
[42] Bodwell J. E., Orti E., Coull J. M., Pappin D. J., Smith L. I., Swift F. Identification of phosphorylated sites in the mouse glucocorticoid receptor J. Biol. Chem 1991 266, N 12:7549– 7555.
[43] Giffin W., Kwast-Welfeld J., Rodda D. J., Prefontaine G. G., Traykova-Andonova M., Zhang Y., Weigel N. L., Lefebvre Y. A., Hache R. J. Sequence-specific DNA binding and transcription factor phosphorylation by Ku Autoantigen/DNA-dependent protein kinase. Phosphorylation of Ser-527 of the rat glucocorticoid receptor J. Biol. Chem 1997 272, N 9:5647–5658.
[44] Krupoves A., Mack D., Deslandres C., Seidman E., Amre D. K. Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease Pharmacogenet. Genomics 2011 21, N 8:454–460.
[45] van West D., Del-Favero J., Deboutte D., Van Broeckhoven C., Claes S. Associations between common arginine vasopressin 1b receptor and glucocorticoid receptor gene variants and HPA axis responses to psychosocial stress in a child psychiatric population Psychiatry Res 2010 179, N 1:64–68.
[46] Bouma E. M., Riese H., Nolte I. M., Oosterom E., Verhulst F. C., Ormel J., Oldehinkel A. J. No associations between single nucleotide polymorphisms in corticoid receptor genes and heart rate and cortisol responses to a standardized social stress test in adolescents: the TRAILS study Behav. Genet 2011 41, N 2:253–261.
[47] Ruiz M., Lind U., Gafvels M., Eggertsen G., Carlstedt-Duke J., Nilsson L., Holtmann M., Stierna P., Wikstrom A. C., Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance Clin. Endocrinol. (Oxf.) 2001 55, N 3:363–371.
[48] Charmandari E., Kino T., Ichijo T., Jubiz W., Mejia L., Zachman K., Chrousos G. P. 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 2007 92, N 10:3986–3990.
[49] Charmandari E., Raji A., Kino T., Ichijo T., Tiulpakov A., Zachman K., Chrousos G. P. A novel point mutation in the ligandbinding 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 2005 90, N 6:3696–3705.
[50] Fingert J. H., Alward W. L., Wang K., Yorio T., Clark A. F. Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders Mol. Vis 2010 16:596–601.
[51] Szczepankiewicz A., Leszczynska-Rodziewicz A., Pawlak J., Rajewska-Rager A., Dmitrzak-Weglarz M., Wilkosc M., Skibinska M., Hauser J. Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder J. Affect. Disord 2011 134, N 1–3:138–144.
[52] Chatzikyriakidou A., Georgiou I., Voulgari P. V., Georgiadis A. N., Argyriou E. S., Drosos A. A. Glucocorticoid receptor variants may predispose to rheumatoid arthritis susceptibility Scand. J. Rheumatol 2009 38, N 1:1–5.
[53] Krishnamurthy P., Romagni P., Torvik S., Gold P. W., Charney D. S., Detera-Wadleigh S., Cizza G.; P. O. W. E. R. (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study Group. Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression Horm. Metab. Res 2008 40, N 3:194–198.
[54] Moons T., Claes S., Martens G. J., Peuskens J., Van Loo K. M., Van Schijndel J. E., De Hert M., van Winkel R. Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs Schizophr. Res 2011 125, N 2–3:187–193.