Alternative titles; symbols
HGNC Approved Gene Symbol: NR3C1
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:143,277,931-143,435,512 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.3 | Glucocorticoid resistance | 615962 | Autosomal dominant | 3 |
The human glucocorticoid receptor belongs to the steroid/thyroid/retinoic acid superfamily of nuclear receptors and functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes positively or negatively (summary by Charmandari, 2011).
Glucocorticoid hormones, like other classes of steroid hormones, exert their cellular action by complexing with a specific cytoplasmic receptor which in turn translocates to the nucleus and binds to specific sites on chromatin. The glucocorticoid receptor (GCCR) was the first transcription factor to be isolated and studied in detail (Muller and Renkawitz, 1991). The glucocorticoid receptor is crucial to gene expression. It is a 94-kD polypeptide and according to one model is thought to have distinct steroid-binding and DNA-binding domains. Weinberger et al. (1985) used expression cloning techniques to select human glucocorticoid receptor cDNA. Weinberger et al. (1985, 1987) pointed out that the glucocorticoid receptor that they cloned is related to the erb-A family of oncogenes (see 190120 and 190160). Cloned members of the erb oncogene family showed a strong relatedness to the DNA-binding domain of the glucocorticoid receptor. A short region of GRL was homologous to certain homeotic proteins of Drosophila.
Hollenberg et al. (1985) identified cDNAs encoding the human glucocorticoid receptor. These DNAs predicted 2 protein forms of 777 (GR-alpha) and 742 (GR-beta) amino acids, which differ in their carboxy termini. The proteins contain a cysteine/lysine/arginine-rich region which may define the DNA-binding domain.
Carlstedt-Duke et al. (1987) analyzed the domain structure of the rat liver GCR protein. The steroid-binding domain, defined by a unique tryptic cleavage, corresponded to the C-terminal protein with the domain border in the region of residue 518. The DNA-binding domain, defined by a region with chymotryptic cleavage sites, was immediately adjacent to the steroid-binding domain with its border in the region of residues 410-414.
Rivers et al. (1999) described GR-gamma, a novel variant of GCCR in which, as a result of alternative splicing, 3 bases are retained from the intron separating exons 3 and 4. These 3 bases code for an additional amino acid (arginine) in the DNA-binding domain of the receptor. Insertion of arginine at this site had previously been shown to decrease transcriptional activation by the GR to 48% that of GR-alpha (Ray et al., 1996). Analysis of cDNA from different tissues showed that GR-gamma is widely expressed at a relatively high level (between 3.8% and 8.7% of total GR).
Oakley et al. (1996) examined the expression, biochemical properties, and physiologic function of GR-beta. They found that the GR-beta message has a widespread tissue distribution. Oakley et al. (1996) demonstrated that GR-beta resides primarily in the nucleus of transfected cells independent of hormone treatment. Oakley et al. (1996) showed that dominant-negative activity occurs in cells that have endogenous GR-alpha receptors. In addition, they demonstrated that the repression of GR-alpha activity occurs with the simple promoter pGRE2CAT, indicating that the repression is a general phenomenon of glucocorticoid-responsive promoters and that glucocorticoid-response-element (GRE)-mediated transcription is actually inhibited.
Of the alpha and beta isoforms of the glucocorticoid receptor generated by alternative splicing, GR-alpha is a ligand-activated transcription factor that, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to a specific glucocorticoid response element (GRE) DNA sequence. In contrast, GR-beta does not bind glucocorticoids and is transcriptionally inactive. Bamberger et al. (1995) demonstrated that GR-beta is able to inhibit the effects of hormone-activated GR-alpha on a glucocorticoid-responsive reporter gene in a concentration-dependent manner. The inhibitory effect appeared to be due to competition for GRE target sites. Since RT-PCR analysis showed expression of GR-beta mRNA in multiple human tissues, GR-beta may be a physiologically and pathophysiologically relevant endogenous inhibitor of glucocorticoid action and may participate in defining the sensitivity of tissues to glucocorticoids.
Roux et al. (1996) found that mutation of isoleucine-747 to threonine in the C-terminal portion of the ligand-binding domain of NR3C1 alters the specificity of the ligand for transactivation. Whereas natural glucocorticoids such as cortisol or corticosterone were completely inactive, synthetic steroids like dexamethasone efficiently stimulated I747T mutant NR3C1-mediated transactivation. The basis for the inability of cortisol to activate I747T was predicted from the canonical 3-dimensional structure of nuclear receptor ligand-binding domains because isoleucine-747 is in the direct vicinity of residues that contribute to the ligand-binding pocket.
Using oligonucleotide-directed mutagenesis, Lind et al. (1996) found functional substitutions of residue 736 with serine (cys736 to ser) and threonine (cys736 to thr). The cys736-to-ser protein showed reduced sensitivity to all hormones tested in transactivation assays and a reduced hormone binding affinity. A correspondence between sensitivity to hormone in transactivation assays and hormone-binding affinity was also observed for the cys736-to-thr protein. The authors concluded that very conservative substitutions of cys736, including serine and threonine, cause variable effects on hormone binding that distinguish between different glucocorticoid steroid hormones.
Diamond et al. (2000) showed, in diverse cell types, that glucocorticoids can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from the androgen receptor (AR; 313700) or huntingtin (HTT; 613004) through specific regulation of gene expression. Wildtype glucocorticoid receptor, as well as C-terminal deletion derivatives, suppressed the aggregation and nuclear localization of these polypeptides, whereas mutations within the DNA-binding domain and the N terminus of GCR abolished this activity. Surprisingly, deletion of a transcriptional regulatory domain within the GCR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcriptional regulator, the GCR. The findings suggested approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.
Welch and Diamond (2001) used wildtype GR and a mutated form of GR (GR-delta-109-317) to study expanded polyglutamine AR protein in different cell contexts. The authors found that wildtype GR promoted soluble forms of the AR protein and prevented nuclear aggregation in NIH 3T3 cells and cultured neurons. In contrast, GR-delta-108-317 decreased polyglutamine protein solubility, and caused formation of nuclear aggregates in nonneuronal cells. Nuclear aggregates recruited the heat-shock protein hsp72 more rapidly than cytoplasmic aggregates, and were associated with decreased cell viability. Limited proteolysis and chemical crosslinking suggested unique soluble forms of the expanded AR protein may underlie these distinct biological activities. The authors hypothesized that unique protein associations or conformations of expanded polyglutamine proteins may determine subsequent cellular effects such as nuclear localization and cellular toxicity.
Webster et al. (2003) reported that 2 proteins that comprise a lethal factor of Bacillus anthracis selectively and specifically repress glucocorticoid receptor and other nuclear hormone receptors, including progesterone receptor (PGR; 607311). This was, it seemed, the first report of a bacterial product interfering with nuclear hormone receptor function. It provides a previously uncharacterized explanation of how such agents might contribute to the pathogenesis of bacterial infections, and may have implications for development of new treatments and prevention of the toxic effects of anthrax.
Glucocorticoid response units are complex and are often located at distant sites relative to the transcription start site in a gene. In their review, Schoneveld et al. (2004) discussed the interaction of GCCR with other transcription factors and the utilization of several GREs for the regulation of gene expression. They also discussed other factors that may influence the activity of the glucocorticoid response unit, such as higher order chromatin structure and nuclear organization.
Revest et al. (2005) found that the effects of stress-related glucocorticoid receptor signaling in mouse hippocampus were mediated by the MAPK pathway and Egr1 (128990).
Hagendorf et al. (2005) investigated whether chronic hypercortisolism, chronic hypocortisolism, or acute, relative hypocortisolism influences the expression levels of GCCR splice variants in mononuclear leukocytes. They found a significant correlation between the expression levels of the 3 GCCR splice variants and between the mRNA levels and the number of receptors per cell. The authors concluded that Cushing syndrome is accompanied by a reversible decrease in GCCR affinity, possibly related to an increased GCCR-beta expression, which may be a compensatory mechanism to glucocorticoid excess. In chronic hypocortisolism, adaptive changes in GCCR status seem to occur at the level of glucocorticoid receptor number.
McKeen et al. (2008) identified FKBPL (617076) as an immunofilin in GR-HSP90 (see 140571) protein complexes and showed that it mediated interaction of the complexes with the dynein motor protein dynamitin (DCTN2; 607376). In GR-expressing DU145 human prostate carcinoma cells, knockdown of FKBPL via small interfering RNA perturbed translocation of GR complexes along microtubules from the cytoplasm to the nucleus in response to the GR ligand dexamethasone. Overexpression of FKBPL in DU145 cells increased GR protein content and transactivation of a reporter gene in response to dexamethasone, but the effect of FKBPL on GR transcriptional activity was cell-line dependent. In L132 cells, which do not express high levels of GR, FKBPL overexpression reduced GR transcriptional activity, and knockdown of FKBPL increased GR transcriptional activity.
Using structural, biochemical, and cell-based assays, Meijsing et al. (2009) showed that glucocorticoid receptor binding sequences, differing by as little as a single basepair, differentially affect glucocorticoid receptor conformation and regulatory activity. Meijsing et al. (2009) proposed that DNA is a sequence-specific allosteric ligand of glucocorticoid receptor that tailors the activity of the receptor toward specific target genes.
Lamia et al. (2011) showed that 2 circadian coregulators, cryptochrome-1 (CRY1; 601933) and cryptochrome-2 (CRY2; 603732), interact with glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of Cry1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, Cry1 and Cry2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase-1 (PCK1; 614168) promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the Pck1 gene was strikingly increased in cryptochrome-deficient livers. Lamia et al. (2011) concluded that their results revealed a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.
Martyn et al. (2012) found that CREBRF (617109) repressed GR transcriptional activity and promoted GR protein degradation in transfected HeLa cells. Confocal microscopy demonstrated colocalization of CREBRF with the GR repressor RIP140 (NRIP1; 602490) in nuclear foci. Martyn et al. (2012) proposed that LRF may work with RIP140 to repress GR transcriptional activity and accelerate GR protein turnover. Additional studies in Crebrf -/- mice suggested that CREBRF plays a critical role in attenuation of the hypothalamic-pituitary-adrenal axis through repression of glucocorticoid stress signaling during parturition and the postpartum period.
Zhang et al. (2013) demonstrated that the RNA-binding protein ZFP36L2 (612053) is a transcriptional target of the GR receptor in burst-forming unit-erythroid (BFU-E) progenitors and is required for BFU-E self renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to mRNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated.
Druker et al. (2013) found that RSUME (RWDD3; 615875) enhanced sumoylation of GCCR by UBC9 (UBE2I; 601661), resulting in enhanced transcription of GCCR-dependent genes. RSUME expression was induced by heat stress, and RSUME was required for heat stress-dependent activation of GCCR target genes. Druker et al. (2013) noted that in other contexts, sumoylation of GCCR inhibits its transcriptional activity.
Corticosteroids have specific effects on cardiac structure and function mediated by mineralocorticoid and glucocorticoid receptors (MR and GR, respectively). Aldosterone and corticosterone are synthesized in rat heart. To see whether they might also be synthesized in the human cardiovascular system, Kayes-Wandover and White (2000) examined the expression of genes for steroidogenic enzymes as well as genes for GR, MR, and 11-hydroxysteroid dehydrogenase (HSD11B2; 614232), which maintains the specificity of MR. Human samples were from left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node, as well as whole adult and fetal heart. Using RT-PCR, mRNAs encoding CYP11A (118485), CYP21 (613815), CYP11B1 (610613), GR, MR, and HSD11B2 were detected in all samples except ventricles, which did not express CYP11B1. CYP11B2 (124080) mRNA was detected in the aorta and fetal heart, but not in any region of the adult heart, and CYP17 (609300) was not detected in any cardiac sample. Levels of steroidogenic enzyme gene expression were typically 0.1% those in the adrenal gland. The authors concluded that these findings are consistent with autocrine or paracrine roles for corticosterone and deoxycorticosterone, but not cortisol or aldosterone, in the normal adult human heart.
Neutrophils are markedly less sensitive to glucocorticoids than are T lymphocytes. Using immunofluorescence, Western blot, and RNA dot blot analyses, Strickland et al. (2001) showed that GR-alpha and GR-beta are both expressed on mononuclear cells and neutrophils, with GR-beta expression somewhat greater than GR-alpha on neutrophils. IL8 (146930) stimulation of neutrophils resulted in a significant increase in GR-beta but not GR-alpha expression in neutrophils. Unlike human neutrophils, mouse neutrophils do not express GR-beta. Transfection of GR-beta into mouse neutrophils led to a significant reduction in the cell death rate when exposed to dexamethasone. Strickland et al. (2001) concluded that the high constitutive and proinflammatory cytokine-inducible upregulation of GR-beta in neutrophils enhances their survival during glucocorticoid treatment of inflammation. They proposed that this knowledge may help in the development of novel antiinflammatory strategies.
Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kappa-B (164011) and the glucocorticoid receptor. Webster et al. (2001) reported the identification of a tumor necrosis factor (TNF)-responsive NF-kappa-B DNA-binding site 5-prime to the GCCR promoter that leads to a 1.5-fold increase in GR-alpha mRNA and a 2.0-fold increase in GR-beta mRNA in HeLaS3 cells, which endogenously express both glucocorticoid receptor isoforms. However, TNF-alpha (191160) treatment disproportionately increased the steady-state levels of the GR-beta protein isoform over GR-alpha, making GR-beta the predominant endogenous receptor isoform. Similar results were observed following treatment of human lymphoid cells with TNF-alpha or interleukin-1 (IL1; see 147760). The increase in GR-beta protein expression correlated with the development of glucocorticoid resistance.
Lee et al. (2015) demonstrated that activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha; 170998) by PPAR-alpha agonists synergizes with the GR to promote BFU-E self-renewal. Over time these agonists greatly increased production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34+ peripheral blood progenitors, with a new and effective culture system being used for the human cells that generated normal enucleated reticulocytes. Although Ppara-null mice showed no hematologic difference from wildtype mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-alpha agonists facilitated recovery of wildtype but not Ppara-null mice from PHZ-induced acute hemolytic anemia. Lee et al. (2015) also found that PPAR-alpha alleviated anemia in a mouse model of chronic anemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-alpha cooccupies many chromatin sites with the GR. When activated by PPAR-alpha agonists, additional PPAR-alpha is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Lee et al. (2015) concluded that their results suggested a novel function of PPAR-alpha in self-renewal of early committed erythroid progenitors.
Kino et al. (2012) showed that human ZNF764 (619524) was required for GR transcriptional activity, as knockdown of ZNF764 in HeLa cells significantly reduced transcriptional activity, whereas ZNF764 overexpression enhanced transcriptional activity. Further analysis suggested that the effect of ZNF764 on GR transcriptional activity involved the coactivator TIF1 (see 603406).
By mapping genomic binding sites for ZNF764 and GR in HeLa cells, Fadda et al. (2017) showed that ZNF764 and GR bound genomic DNA in close proximity with each other and distantly from transcription start sites of nearby genes. The presence or absence of ZNF764 differentially regulated binding of GR to genomic DNA and GR transcriptional activity on responsive genes. Immunoprecipitation analysis in HeLa cells revealed that ZNF764 and GR physically interacted through the KRAB domain of ZNF764 and the C-terminal ligand-binding domain of GR. By interacting with GR, ZNF764 modulated GR transcriptional activity by directing its actions toward certain biologic pathways.
Bledsoe et al. (2002) reported the crystal structure of the human GR ligand-binding domain (LBD; residues 521 to 777) bound to dexamethasone and a coactivator motif (the third LxxLL motif) derived from transcriptional intermediary factor-2 (TIF2; 601993). Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular beta sheet. Functional studies demonstrated that the dimer interface is important for GR-mediated activation. The structure also revealed an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand-binding pocket that explains its selectivity for endogenous steroid hormones.
Although the GRL gene had previously been reported to consist of 10 exons (Encio and Detera-Wadleigh, 1991), Oakley et al. (1996) suggested that the GRL sequences formerly identified as exon 9-alpha, intron J, and exon 9-beta comprise 1 large terminal exon (exon 9) of approximately 4.1 kb and that the GRL gene is organized into 9 rather than 10 exons.
Breslin et al. (2001) isolated and characterized a novel human GCCR gene sequence (GR 1Ap/e), which was distinct from previously identified human GCCR promoter and coding sequences. The 2,056-bp GR 1Ap/e sequence is approximately 31 kb upstream of the human GCCR coding sequence. This sequence contains a novel promoter of 1,075 bp and untranslated exon sequence of 981 bp. Alternative splicing produces 3 different GR 1A-containing transcripts, 1A1, 1A2, and 1A3. GCCR transcripts containing exon 1A1, 1A2, 1B, and 1C are expressed at various levels in many cancer cell lines, while the exon 1A3-containing GR transcript is expressed most abundantly in blood cell cancer cell lines. Glucocorticoid hormone treatment causes an upregulation of exon 1A3-containing GCCR transcripts in CEM-C7 T-lymphoblast cells and a downregulation of exon 1A3-containing transcripts in IM-9 B-lymphoma cells. Much of the basal promoter-activating function is found in the +41/+269 sequence, which contains 2 deoxyribonuclease I footprints (FP5 and FP6). FP5 is an interferon regulatory factor-binding element, and it contributes significantly to basal transcription rate, but it is not activated by steroid. FP6 resembles a glucocorticoid response element and can bind GR-beta.
Gehring et al. (1984) and Gehring et al. (1985) mapped the GRL gene to chromosome 5 by study of hybrids of a human lymphoblastic cell line (that is glucocorticoid-sensitive and contains glucocorticoid receptors of wildtype characteristics) and a mouse lymphoma cell line (that is resistant to lysis by glucocorticoids because of a mutant receptor that exhibits abnormal DNA binding).
Weinberger et al. (1985) used a cDNA clone in connection with a panel of somatic hybrid cells with various rearrangements involving chromosome 5 to assign GCCR to 5q11-q13. However, Francke and Foellmer (1989) demonstrated by in situ hybridization that the GRL gene is located on 5q31-q32. The new assignment is consistent with linkage to a DNA marker that maps to the same region (Giuffra et al., 1988) and also with human/mouse comparative mapping data. From family linkage studies, Giuffra et al. (1988) likewise concluded that the GRL locus is located toward the end of the long arm of chromosome 5.
Hollenberg et al. (1985) confirmed the assignment of a glucocorticoid receptor gene to chromosome 5 by Southern analysis of a hybrid cell line containing only chromosome 5. In addition, 2 fragments (formed with EcoRI and Hind III) were found in total human DNA and not in the hybrid line. To map these, Hollenberg et al. (1985) used a dual-laser fluorescence-activated cell sorter and spot-blotting. This confirmed the assignment to chromosome 5 and in addition showed hGR sequences on chromosome 16. The assignment to chromosome 16 was confirmed by Southern analysis of DNA from a mouse erythroleukemia cell line containing human chromosome 16. The authors concluded that both the alpha and beta receptor proteins are probably encoded by a single gene on chromosome 5 and generated by alternative splicing. In addition they concluded that a gene on chromosome 16 contains homology to the glucocorticoid receptor gene, at least between nucleotides 570 and 1,640. This could be the receptor gene for a related steroid, a processed gene or pseudogene, or a gene with other function that shares a domain with the GRL gene. See 138060.
By in situ hybridization with a biotinylated cDNA probe, Theriault et al. (1989) localized the GRL gene to chromosome 5q31. The assignment was confirmed by hybridization to chromosomes from an individual with a balanced reciprocal translocation (5;8)(q31;q13). Using chromosome-5-linked DNA probes to study somatic cell hybrids retaining partial chromosome 5 and clinical samples from patients with acquired deletions of 5q, Huebner et al. (1990) concluded that the GRL gene is telomeric to CSF2 (138960) and centromeric to CSF1R (164770)/PDGFRB (173410), near ECGF (131220).
Generalized Glucocorticoid Resistance
In affected members of the kindred originally reported by Vingerhoeds et al. (1976) with generalized glucocorticoid deficiency (GCCR; 615962), Hurley et al. (1991) identified a heterozygous missense mutation in the GCR gene (D641V; 138040.0001).
In all 3 affected members of a Dutch kindred with glucocorticoid resistance, Karl et al. (1993) identified heterozygosity for a 4-bp deletion in the GCR gene (138040.0002).
Bray and Cotton (2003) reported that a total of 15 missense, 3 nonsense, 3 frameshift, 1 splice site, and 2 alternatively spliced mutations had been reported in the NR3C1 gene to be associated with glucocorticoid resistance; 16 polymorphisms had also been reported.
Stevens et al. (2004) tested the potential involvement of the NR3C1 gene in mediating glucocorticoid sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GCCR gene was determined in 216 Caucasians from the United Kingdom, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GCCR gene, with only 4 haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a 3-marker haplotype across intron B to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol versus 23% in the combined other quartiles. The authors concluded that a 3-point haplotype within intron B is associated with enhanced sensitivity to glucocorticoids and that this haplotype may help predetermine variation in clinical response to glucocorticoid therapy and also assist the understanding of diseases related to glucocorticoid production.
Van den Akker et al. (2006) studied the effect of the GCCR haplotype characterized by the GR-9-beta polymorphism rs6198 on GCCR transactivation and transrepression. The 53 persons carrying the GR-9-beta haplotype without ER22/23EK (138040.0011) had no significant differences in their BMI, waist-to-hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with 113 noncarriers. Ex vivo, GCCR-induced upregulation of GCCR-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9-beta homozygotes, whereas the downregulation of IL2 (147680) expression via transrepression was decreased. Van den Akker et al. (2006) concluded that persons carrying the GR-9-beta haplotype seem to have a decreased GCCR transrepression with normal transactivation.
DeRijk et al. (2006) studied the role of a GCCR common polymorphism (I180V) in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. Carriers of the 180V allele showed higher saliva (p less than 0.01), plasma cortisol (p less than 0.01), and heart rate responses (p less than 0.05) to the Trier Social Stress Test than noncarriers (I180I). In vitro testing of the 180V allele revealed a mild loss of function using cortisol as a ligand, compared with the 180I allele. DeRijk et al. (2006) concluded that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the 180V variant.
Corticotrophinomas
Because cortisol resistance can be caused by genetic abnormalities in the GRL gene, Huizenga et al. (1998) investigated whether the insensitivity of corticotropinomas to cortisol is also caused by de novo GRL mutations. Except for 1 silent point mutation, they did not identify mutations in the GRL gene in leukocytes or corticotropinomas from 22 patients with Cushing disease. Of the 22 patients, 18 were heterozygous for at least 1 polymorphism, and 6 of the 18 had loss of heterozygosity (LOH) in the tumor DNA. They concluded that LOH at the GRL locus is a relatively frequent phenomenon in pituitary adenomas of patients with Cushing disease and that this may explain the relative resistance of the adenoma cells to the inhibitory feedback action of cortisol on ACTH secretion.
Pepin et al. (1992) developed transgenic mice in which antisense RNA complementary to the 3-prime noncoding region of the glucocorticoid receptor mRNA led to reduced glucocorticoid receptor capacity and function, predominantly in neuronal tissue. Montkowski et al. (1995) demonstrated that the transgenic mice have profound behavioral changes and elevated plasma corticotropin concentrations in response to stress. Treatment with moclobemide, an inhibitor of monoamine oxidase type A (309850), reversed the behavioral deficits in this mouse model.
Since the glucocorticoid receptor can influence transcription both through DNA-binding-dependent and -independent mechanisms, Reichardt et al. (1998) attempted to separate these modes of action by introducing the arg458-to-thr point mutation into the glucocorticoid receptor by gene targeting using the Cre/loxP system. This mutation impairs dimerization and therefore GRE-dependent transactivation, while functions that require cross-talk with other transcription factors, such as transrepression of AP-1-driven genes, remain intact. In contrast to GR-/- mice, these mutants, termed GR-dim, are viable, revealing the in vivo relevance of DNA-binding-independent activities of the glucocorticoid receptor. The GR-dim/dim mice lose the ability to transactivate gene transcription by cooperative DNA binding but retain the repressing function of the corticosteroid receptor. Furthermore, the development and function of the adrenal medulla are not impaired in these mice.
The glucocorticoid receptor controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune, and nervous system responses and ensure an adequate profile of transcription. In the brain, glucocorticoid receptor has been thought to modulate emotional behavior, cognitive functions, and addictive states. These aspects could not be studied in the absence of functional glucocorticoid receptor because inactivation of the Grl1 gene in mice causes lethality at birth. Therefore, Tronche et al. (1999) generated tissue-specific mutations of this gene using the Cre/loxP-recombination system. This allowed them to generate viable adult mice with loss of glucocorticoid receptor function in selected tissues. Loss of glucocorticoid receptor function in the nervous system impaired regulation of the hypothalamus-pituitary-adrenal axis, resulting in increased glucocorticoid levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of glucocorticoid receptor in the nervous system provided genetic evidence for the importance of glucocorticoid receptor signaling in emotional behavior because mutant animals showed an impaired behavioral response to stress and displayed reduced anxiety.
Using a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, McNally et al. (2000) observed targeting of the receptor to response elements in mouse cells. Photobleaching experiments provided direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. Thus, McNally et al. (2000) concluded that the interaction of regulatory proteins with target sites in chromatin is a more dynamic process than had been believed.
Brewer et al. (2003) used Lck (153390) promoter-driven, Cre recombinase-mediated excision of exon 2 of the Gccr gene to generate healthy mice lacking Gccr only in T cells and thymus to avoid perinatal mortality and to maintain systemic corticosterone responses. Gccr was dispensable for T-cell development, but administration of a T-cell stimulus or superantigen to mutant mice, but not control mice, resulted in high mortality that could not be rescued by dexamethasone or anti-Ifng (147570). Microarray and ribonuclease protection analyses suggested that endogenous glucocorticoids are required for transcriptional suppression of Ifng, but not Tnf or Il2 (147680), in T cells. Inhibition of Cox2 (600262) protected mice from lethality without affecting Ifng levels. Histologic analysis revealed that T-cell stimulation in mutant mice caused significant damage to the gastrointestinal tract, particularly the cecum, but little or no damage in other tissues. Brewer et al. (2003) concluded that Gccr function in T cells is essential for survival during polyclonal T-cell activation. Furthermore, they suggested that Cox2 inhibition may be useful for treatment of glucocorticoid insufficiency or resistance in patients with toxic shock syndrome (see 607395), graft-versus-host disease (GVHD; see 614395), or other T-cell activating processes.
Tronche et al. (2004) found that mice with targeted disruption of Gccr in hepatocytes showed dramatically reduced body size due to impaired Stat5 (601511)-dependent growth hormone signaling. Mice with a mutant Gccr deficient in DNA binding but still able to interact with Stat5 showed normal body size and normal levels of Stat5-dependent transcription. Tronche et al. (2004) concluded that GCCR acts as a coactivator for STAT5-dependent transcription upon growth hormone stimulation.
Wei et al. (2004) showed that the glucocorticoid receptor modulates the range and stability of emotions, features of emotional responsiveness. They generated transgenic mice overexpressing Gccr specifically in forebrain. These mice displayed a significant increase in anxiety-like and depressive-like behaviors relative to wildtype, and were also supersensitive to antidepressants and showed enhanced sensitization to cocaine. Thus, mice overexpressing Gccr in forebrain have a consistently wider than normal range of reactivity in both positive and negative emotionality tests. This phenotype is associated, in specific brain regions, with increased expression of genes relevant to emotionality: corticotropin-releasing hormone (122560), 5-hydroxytryptamine receptor 1A (109760), and transporters of serotonin (182138), norepinephrine (163970), and dopamine (126455). Thus, Gccr overexpression in forebrain causes higher 'emotional lability' secondary to a unique pattern of molecular regulation. Wei et al. (2004) concluded that natural variations in GCCR gene expression can contribute to the fine tuning of emotional stability or lability and may play a role in bipolar disorder (see 125480).
Barik et al. (2013) bred mice with selective inactivation of the gene encoding the glucocorticoid receptor along the dopamine pathway, and exposed them to repeated aggressions. Glucocorticoid receptor in dopaminoceptive but not dopamine-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiologic neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of dopamine-releasing neurons fully restored social interaction in socially defeated wildtype mice. Barik et al. (2013) concluded that their data suggested a glucocorticoid receptor-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicated the glucocorticoid receptor as a link between stress resiliency and dopaminergic tone.
Niwa et al. (2013) described an underlying mechanism in which glucocorticoids link adolescent stressors to epigenetic controls in neurons. In a mouse model of this phenomenon, a mild isolation stress affects the mesocortical projection of dopaminergic neurons in which DNA hypermethylation of the tyrosine hydroxylase (191290) gene is elicited, but only when combined with a relevant genetic risk for neuropsychiatric disorders. These molecular changes were associated with several neurochemical and behavioral deficits that occur in this mouse model, all of which were blocked by a glucocorticoid receptor antagonist. Niwa et al. (2013) concluded that the biology and phenotypes of the mouse models resemble those of psychotic depression.
In the kindred with generalized glucocorticoid resistance (GCCR; 615962) originally reported by Vingerhoeds et al. (1976) and studied by Chrousos et al. (1982, 1983) and Lipsett et al. (1985), Hurley et al. (1991) sequenced the glucocorticoid receptor from 3 affected members. A change at nucleotide 2054 predicted substitution of valine for aspartic acid at amino acid 641. The severely affected propositus was homozygous for the mutation, whereas his mildly affected son and nephew were heterozygous. The point mutation was in the steroid-binding domain of the receptor.
In 3 sibs of a Dutch kindred with glucocorticoid resistance (GCCR; 615962), Karl et al. (1993) found that 1 NR3C1 allele had a 4-bp deletion that removed the donor splice site affecting the last 2 bases of exon 6 and the first 2 nucleotides of intron 6. The father, whose DNA was not examined, and 3 of his 5 children were affected. Affected members had hypercortisolism and approximately half of normal glucocorticoid receptors. The proband was a daughter with manifestations of hyperandrogenism. Furthermore, in the proband, in 1 of her affected brothers, and in her unaffected sister, Karl et al. (1993) found a single nucleotide substitution (1220A-G; asn363 to ser; 138040.0007) in exon 2 of the NR3C1 allele. Transfection studies indicated that the amino acid substitution did not alter the function of the glucocorticoid receptor. The presence of the null allele in this family was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism.
Ashraf and Thompson (1993) showed that 2 glucocorticoid-resistant cell lines were hemizygous for a leu753-to-phe mutation in the NR3C1 gene. Both were derived from a wildtype cell line heterozygous for this mutation; the resistant cell lines had suffered the loss of the normal allele.
Koper et al. (1997) identified a polymorphism, located at nucleotide position 1220 (AAT to AGT), that results in an asparagine-to-serine change in codon 363 (N363S) of the NR3C1 protein. Huizenga et al. (1998) investigated whether this polymorphism is associated with altered sensitivity to glucocorticoids. In a group of 216 elderly persons, they identified 13 heterozygotes for the N363S polymorphism by PCR/SSCP analysis. Thus, they found the polymorphism in 6.0% of the studied population. Huizenga et al. (1998) concluded that individuals carrying this polymorphism were clinically healthy, but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Huizenga et al. (1998) speculated that life-long exposure to the mutated allele may be accompanied by an increased body mass index and a lowered bone mineral density in the lumbar spine with no effect on blood pressure.
Dobson et al. (2001) investigated the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United Kingdom. Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%; 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. These data showed a significant association of the 363S allele with increased waist-to-hip ratio in males but not in females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, or glucose tolerance status. The authors concluded that this GR polymorphism may contribute to central obesity in men.
Russcher et al. (2005) examined the effects of the N363S polymorphism on glucocorticoid sensitivity at the level of gene expression in functional assays. The N363S polymorphism, associated with increased glucocorticoid sensitivity, resulted in a significantly increased transactivating capacity, both in vitro and ex vivo. The N363S polymorphism did not seem to influence the transrepressing capacity of the glucocorticoid receptor.
In a population of 295 South Asians living in the United Kingdom consisting of 35% people of Indian origin, 42% of Pakistani origin, and 19% Bangladeshi origin, Syed et al. (2004) detected a prevalence of 0.3% of the 363S allele (2 heterozygous subjects). Both subjects had raised body mass index and central obesity. The authors concluded that given its prevalence, the N363S polymorphism is unlikely to be an important factor in obesity and/or dysmetabolic traits in people of South Asian origin living in the United Kingdom.
Majnik et al. (2006) found that the carrier frequency of the N363S variant in patients with bilateral adrenal incidentalomas was markedly and significantly higher than that in control subjects (20.5 vs 7.8%, P less than 0.05), but not in those with unilateral adrenal incidentalomas (7.1%) or in patients with type 2 diabetes (13.0%).
Jewell and Cidlowski (2007) studied the biologic relevancy of the N363S variant on GCCR function. Functional assays with reporter gene systems and homologous downregulation revealed only minor differences between the wildtype human GCCR and N363S receptors in both transiently and stably expressing cell lines. However, examination of the 2 receptors by human gene microarray analysis revealed a unique gene expression profile for N363S. Jewell and Cidlowski (2007) noted that several of the regulated genes supported a potential role for the N363S polymorphism in human diseases.
Karl et al. (1996) reported a patient with sporadic generalized glucocorticoid resistance (GCCR; 615962) who, at age 33, presented with infertility and hypertension. The patient's clinical and biochemical picture was more severe than would be expected from the loss of 1 GCCR allele activity. Two years after initiation of an effective dexamethasone regimen, this patient developed full-blown Cushing syndrome secondary to an ACTH-secreting pituitary tumor, with a further 8-fold increase in serum cortisol. The patient had a heterozygous missense mutation in exon 4 of the glucocorticoid receptor gene resulting in a nonconservative ile559-to-asn (I559N) amino acid substitution. This allele had negligible ligand binding, was transcriptionally extremely weak, and exerted a trans-dominant-negative effect on the transactivational activity of the wildtype GCCR, causing severe glucocorticoid resistance in the heterozygous state (Kino et al., 2001).
To further elucidate the mechanism of trans-dominance of the I559N mutant receptor and its clinical manifestations, Kino et al. (2001) examined its trafficking in living cells using N-terminal fusion of green fluorescent protein (GFP) to wildtype and I559N mutant glucocorticoid receptor. The chimeric mutant protein product was predominantly localized in the cytoplasm, and only high doses or prolonged glucocorticoid treatment triggered complete nuclear import that took 180 minutes, versus 12 minutes for the wildtype construct. Furthermore, the mutant construct inhibited nuclear import of the wildtype, suggesting that its trans-dominant activity on the wildtype receptor is probably exerted at the process of nuclear translocation.
Vottero et al. (2002) reported a French kindred with familial glucocorticoid resistance (GCCR; 615962) in which affected members had a heterozygous T-to-G transversion at nucleotide 2373 of exon 9-alpha of the GCCR gene, resulting in an ile747-to-met (I747M) substitution. This mutation was located close to helix 12, at the C terminus of the ligand-binding domain, which has a pivotal role in the formation of activation function (AF)-2, a subdomain that interacts with p160 coactivators. The affinity of the mutant GCCR for dexamethasone was decreased by about 2-fold, and its transcriptional activity on the glucocorticoid-responsive mouse mammary tumor virus promoter was compromised by 20- to 30-fold. In addition, the mutant GCCR functioned as a dominant-negative inhibitor of wildtype receptor-induced transactivation. The mutant GR through its intact AF-1 domain bound to a p160 coactivator, but failed to do so through its AF-2 domain. Overexpression of a p160 coactivator restored the transcriptional activity and reversed the negative transdominant activity of the mutant GCCR. The authors concluded that the mutant receptor has an ineffective AF-2 domain, which leads to an abnormal interaction with p160 coactivators and a distinct nuclear distribution of both.
Mendonca et al. (2002) reported a female patient with ambiguous genitalia, the child of second-cousin parents, who had been treated as a 21-hydroxylase deficiency (201910) case since the age of 5 years. She had very high levels of plasma ACTH and high levels of cortisol, androstenedione, and 17-hydroxyprogesterone. Her cortisol and 17-hydroxyprogesterone levels were not compatible with the diagnosis of classic congenital adrenal hyperplasia; furthermore, cortisol was not properly suppressed after dexamethasone administration. Her laboratory evaluation indicated a diagnosis of glucocorticoid resistance (GCCR; 615962). A homozygous T-to-C substitution at nucleotide 1844 in exon 5 of the GR gene was identified in the patient, which caused a valine-to-alanine substitution at amino acid 571 (V571A) in the ligand domain of the receptor. Her parents and an older sister were heterozygous for this mutation. The ala571 allele had a 6-fold reduction in binding affinity compared with the wildtype receptor. Mendonca et al. (2002) concluded that this was the first reported case of female pseudohermaphroditism caused by a novel GR gene mutation and that this phenotype indicates that pre- and postnatal virilization can occur in females with the glucocorticoid resistance syndrome.
Koper et al. (1997) identified a polymorphism consisting of 2 linked point mutations in the glucocorticoid receptor gene. The first mutation, a G-to-A transition in codon 22, is silent, with both GAG and GAA coding for glutamic acid (E). The second mutation changes codon 23 from arginine (R) to lysine (K) (AGG-AAG). Van Rossum et al. (2002) found an association of this polymorphism with relative resistance to glucocorticoids (GCCR; 615962), and in a population-based study in the elderly observed that carriers of the 22/23EK (ER22/23EK) polymorphism had better insulin sensitivity and lower total and low density lipoprotein cholesterol levels. They also found the frequency of the ER22/23EK allele to be higher in the elder half of the studied population, which suggested a survival advantage. In a separate population of 402 elderly Dutch men, van Rossum et al. (2004) found that after 4 years of follow-up 19.2% of the noncarriers had died, whereas none of the 21 ER22/23EK carriers had died. ER22/23EK carriers also had lower serum C-reactive protein (123260) levels, possibly reflecting improved cardiovascular status.
Van Rossum et al. (2004) investigated the association of the ER22/23EK polymorphism with differences in body composition and muscle strength in a cohort of 350 subjects who were followed from age 13 to 36 years. They identified 27 (8%) heterozygous ER22/23EK carriers. In males at 36 years of age, they found that ER22/23EK carriers were taller, had more lean body mass, greater thigh circumference, and more muscle strength in arms and legs. They observed no differences in body mass index or fat mass. In females, waist and hip circumferences tended to be smaller in ER22/23EK carriers at the age of 36 years, but no differences in body mass index were found. The authors concluded that the ER22/23EK polymorphism is associated with a sex-specific, beneficial body composition at young adult age, as well as greater muscle strength in males.
Russcher et al. (2005) examined the effects of the ER22/23EK polymorphism on glucocorticoid sensitivity at the level of gene expression in functional assays. The ER22/23EK polymorphism produced a significant reduction of transactivating capacity in both transfection experiments and in peripheral blood mononuclear lymphocytes of carriers of this polymorphism. The ER22/23EK polymorphism did not seem to influence the transrepressing capacity of the glucocorticoid receptor.
Finken et al. (2007) tested the effects of the R23K (ER22/23EK) and N363S (138040.0007) polymorphisms in the GCCR gene, associated with decreased and increased sensitivity to cortisol, respectively, on linear growth and the adult metabolic profile in a cohort of 249 men and women born less than 32 weeks' gestation and followed up prospectively from birth until 19 years of age. The 23K variant, present in 24 individuals, was associated with lower fasting insulin levels and a lower homeostatic model assessment for insulin resistance index, as well as with a taller stature from the age of 1 year. Carriers of the 23K variant showed complete catch-up growth between the ages of 3 months and 1 year, and attained height was similar to the population reference mean, whereas stature in noncarriers was on average 0.5 standard deviation below this mean. Finken et al. (2007) concluded that carriers of the 23K variant are, at least in part, protected against postnatal growth failure and insulin resistance after preterm birth.
In a 29-year-old woman with generalized glucocorticoid resistance (GCCR; 615962) who presented with a long-standing history of fatigue, anxiety, hyperandrogenism, and hypertension, Charmandari et al. (2005) found a heterozygous T-to-C transition at nucleotide position 2318 in exon 9 of the GR-alpha gene, which resulted in substitution of leucine by proline at amino acid position 773 (L773P) in the ligand-binding domain of the receptor. Compared with the wildtype receptor, the mutant L773P GR-alpha demonstrated a 2-fold reduction in the ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a dominant-negative effect on the wildtype receptor, had a 2.6-fold reduction in the affinity for ligand, showed delayed nuclear translocation (30 vs 12 min), and, although it preserved its ability to bind to DNA, displayed an abnormal interaction with the GR-interacting protein-1 coactivator (NCOA2; 601993) in vitro. The authors concluded that the C terminus of the ligand-binding domain of GR-alpha is important in conferring transactivational activity by altering multiple functions of this composite transcription factor.
In a 41-year-old woman with primary cortisol resistance (GCCR; 615962), Ruiz et al. (2001) identified heterozygosity for a 1430G-A transition in exon 4 of the NR3C1 gene, resulting in an arg477-to-his (R477H) substitution in the second zinc finger in the DNA-binding domain of the receptor. The mutant showed no transactivating capacity.
Charmandari et al. (2006) studied the mechanisms through which the R477H and G779S (138040.0014) mutations in the DNA- and ligand-binding domains, respectively, affect glucocorticoid signal transduction and concluded that the mutants cause generalized glucocorticoid resistance by affecting different functions of the glucocorticoid receptor, which span the cascade of the GR signaling system.
In a 31-year-old woman with primary cortisol resistance (GCCR; 615962), Ruiz et al. (2001) identified heterozygosity for a 2035G-A transition in exon 8 of the NR3C1 gene, resulting in a gly679-to-ser (G679S) substitution in the ligand-binding domain of the receptor. The mutant showed reduced transactivation capacity compared to wildtype.
See 138040.0013 and Charmandari et al. (2006).
In a boy with generalized glucocorticoid resistance (GCCR; 615962), Charmandari et al. (2007) identified a 2209T-C transition in exon 9 of the GR-alpha gene, resulting in a phe737-to-leu (F737L) substitution within helix 11 of the ligand-binding domain of the protein. Compared to wildtype, the mutant receptor demonstrated decreased affinity for the ligand, marked delay in nuclear translocation, and/or abnormal interaction with the GR-interacting protein-1 coactivator (NCOA2; 601993). Charmandari et al. (2007) concluded that these findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity.
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