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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"In a study of patients with depression, carrier of the ER22/23EK polymorphism had higher rates of recurrent major depression episodes and responded faster to treatment with antidepressants [63,64]. A possible explanation could be the higher concentration of the less active GR variant which could lead to GC resistance . An association between the BclI polymorphism and major depression has been found in several studies. "
[Show abstract][Hide abstract]ABSTRACT: Glucocorticoids (GCs) are involved in a large number of the physiological changes associated with metabolic syndrome and certain psychiatric illness. Although significance is often given to the concentration of GC, its biological action is determined by the activation of intracellular GC receptors (GR). Genetic polymorphisms of the GR and the large array of GR related cofactors can directly or indirectly affect the pathophysiology and evolution of these conditions. This review will discuss the effects of GR mutations on metabolic syndrome and psychotic depression.
Full-text · Article · Mar 2016 · The Journal of Steroid Biochemistry and Molecular Biology
"This polymorphism has been associated with relative GC resistance (Russcher et al., 2005a; van Rossum et al., 2002). In vitro analyses have associated this SNP with reduced transactivating capacity of the GR due to a higher expression of the GR-A isoform (Russcher et al., 2005b). The N363S polymorphism results from one nucleotide substitution in codon 363 of exon 2, and the subsequent alteration from asparagine (N) to serine (S) (Koper et al., 1997 ). "
[Show abstract][Hide abstract]ABSTRACT: CASTRO-VALE, I., E.F.C. van Rossum, J.C. Machado, R. Mota-Cardoso and D. Carvalho. Genetics of glucocorticoid regulation and posttraumatic stress disorder − what do we know? NEUROSCI BIOBEHAV REV 43 (1) XXX–XXX, 2014.- Posttraumatic stress disorder (PTSD) develops in a small proportion of those who have been exposed to a traumatic event. Genetic factors are estimated to be responsible for 30% of the variance in PTSD risk. Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis in PTSD has been found, particularly hypersensitivity of the glucocorticoid receptor (GR). In this review we aim to understand the genetic factors that influence glucocorticoid function in PTSD. Glucocorticoid action is regulated by a corticotrophin-releasing hormone, arginine vasopressin (AVP)/oxytocin pathway, GR, and regulators such as co-chaperone FKBP5. Single nucleotide polymorphisms (SNPs) in the GR gene, CRHR1 gene and FKBP5 gene affect HPA-axis sensitivity. The GR gene SNP BclI has been associated with hypersensitivity to glucocorticoids and PTSD symptoms. FKBP5 gene SNPs interacted with childhood adversity to moderate PTSD risk and in particular, the rs9470080 SNP was independently associated with lifetime PTSD. SNPs in the CRHR1 gene were also associated with PTSD risk. Gene-environment interaction studies have highlighted the importance of multifactorial vulnerability in PTSD, with epigenetic mechanisms contributing to the equation.
No preview · Article · Feb 2016 · Neuroscience & Biobehavioral Reviews
"Furthermore, recent findings from in vitro and in vivo studies have demonstrated the important new role of old molecules, such as the serumand glucocorticoid-inducible kinase 1 (SGK1) [16,17] and FK506 -binding protein 51 (FKBP5) [18,19], in tissue sensitivity to glucocorticoids and associated pathologic conditions. In addition to protein-protein interactions, tissue responsiveness to glucocorticoids has become more complicated since the identification and functional characterization of hGR polymorphisms2021222324. Interestingly, MR polymorphisms may also play some roles in tissue glucocorticoid sensitivity . "
[Show abstract][Hide abstract]ABSTRACT: Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.
Full-text · Article · Aug 2014 · BMC Endocrine Disorders