Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism. Mol Endocrinol

Department of Internal Medicine, Room Ee 593, Erasmus MC, University Medical Center Rotterdam, Molewaterplein 40, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Molecular Endocrinology (Impact Factor: 4.2). 08/2005; 19(7):1687-96. DOI: 10.1210/me.2004-0467
Source: PubMed

ABSTRACT One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure.

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Available from: Elisabeth FC van Rossum, Aug 18, 2015
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    • "Moreover, gender-specific effects of genes have been associated with vulnerability to stress and depression (Silberg et al. 1999; Kendler et al. 2006), and the underlying mechanisms might involve interactions of female sex hormones with corticoid receptors. The ER22/23EK (rs6189/rs6190) SNPs (G to A) in exon 2 of the GR gene (Russcher et al. 2005) was associated with corticoid resistance in a pharmacological challenge (Van Rossum et al. 2004), resulting in higher post-dexamethasone cortisol levels. In men, the G allele of the BclI SNP in the GR gene was associated with blunted salivary cortisol responses compared to men homozygous for the C allele (Wüst et al. 2004; Kumsta et al. 2007; Ising et al. 2008). "
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    ABSTRACT: Previously, sequence variation in the glucocorticoid (GR) and mineralocorticoid (MR) receptor genes (NR3C1 and NR3C2, respectively) have been found to be associated with physiological stress responses to social stress tests in small samples of adult men and oral contraceptives (OC) using women. Associations between single nucleotide polymorphisms (SNPs) in the GR (23EK-rs6190, 9beta-rs6198, BclI-rs4142324) and the MR gene (I180V-rs5522 and -2G/C (rs2070951) with cortisol and heart rate responses to a performance-related social stress task (public speaking and mental arithmetic) were examined in a large sample (n = 553) of adolescents (15-17 years). To make comparisons with previous findings, associations were tested in boys (n = 277), free-cycling (FC) girls (n = 183) and OC users (n = 93). None of the previously reported associations in adults could be replicated in this large adolescent sample. Explanations for non-replication are discussed.
    Behavior Genetics 03/2011; 41(2):253-61. DOI:10.1007/s10519-010-9385-6 · 2.84 Impact Factor
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    • "Upon further analysis, Russcher et al. discovered that the ER22/23EK GR polymorphism facilitated the expression of GRα-A, but had no effect on the expression of the GRα-B translational isoform (Russcher et al., 2005b). Since some studies have shown that GRα-A is transcriptionally less active when compared to GRα-B (Yudt et al., 2001), these molecular data suggest that the relative inactivity of ER22/23EK results from decreased relative levels of GRα-B and that ER22/23EK may correlate with glucocorticoid insensitivity (Russcher et al., 2005b). Although ER22/23EK was not associated with differences in responsiveness to exogenous glucocorticoids in ALL (Tissing et al., 2005c), adult carriers of the ER22/23EK polymorphism were shown to have decreased incidence of type 2 diabetes and decreased risk for cardiovascular disease (van Rossum et al., 2004a; van Rossum et al., 2004b). "
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    ABSTRACT: Glucocorticoid receptor agonists are mainstays in the treatment of various malignancies of hematological origin. Glucocorticoids are included in therapeutic regimens for their ability to stimulate intracellular signal transduction cascades that culminate in alterations in the rate of transcription of genes involved in cell cycle progression and programmed cell death. Unfortunately, subpopulations of patients undergoing systemic glucocorticoid therapy for these diseases are or become insensitive to glucocorticoid-induced cell death, a phenomenon recognized as glucocorticoid resistance. Multiple factors contributing to glucocorticoid resistance have been identified. Here we summarize several of these mechanisms and describe the processes involved in generating a host of glucocorticoid receptor isoforms from one gene. The potential role of glucocorticoid receptor isoforms in determining cellular responsiveness to glucocorticoids is emphasized.
    Molecular and Cellular Endocrinology 11/2008; 300(1-2):7-16. DOI:10.1016/j.mce.2008.10.001 · 4.24 Impact Factor
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    • "One variant located in exon 2 of the NR3C1 gene consists of two linked single nucleotide polymorphisms (SNPs), one in codon 22 and one in codon 23, giving rise to a silent amino acid change (E22E, rs6189) and a conservative amino acid change (R23K, rs6190), respectively. This variant induces a change in the ratio of the short and the long GR protein and causes a decreased sensitivity to dexamethasone [Russcher et al., 2005]. "
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    ABSTRACT: Glucocorticoid receptor (GR) plays a major role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) system; HPA dysregulation represents the most consistent biological pattern of depression. Multiple functional polymorphisms are known for the GR gene, which might influence the development of unipolar depression. Previous studies reported associations to some variants in this gene but not consistently so. We investigated seven genetic polymorphisms in the GR gene (NR3C1) located in the putative promoter, exon 2 and intron 2 region. Study populations were 322 German inpatients with recurrent unipolar depression, and 298 German controls recruited from the general population. The relationships between intermediate phenotypes (hippocampal and amygdala volumes) and NR3C1 DNA sequence variants were additionally explored in a subpopulation of patients. We found association between the diagnosis of depression and DNA sequence variants in intron 2 as well as in the 5' region of the NR3C1 gene but not for the previously studied exon 2 and putative promoter variants (global test after control of multiple testing, P = 0.02). In patients, diagnosis-related alleles were also associated to hippocampal volume reduction and amygdala volume variation. Unipolar depression is associated with DNA variants of the NR3C1 gene in our population. Neurobiological underpinnings of depression as volumetric reductions of the hippocampus may also be mediated by variants in this gene.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2008; 147B(6):836-43. DOI:10.1002/ajmg.b.30709 · 3.27 Impact Factor
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