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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
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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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    • "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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