Increased Expression of the Glucocorticoid Receptor-A Translational Isoform as a Result of the ER22/23EK Polymorphism

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: 4.02). 08/2005; 19(7):1687-96. DOI: 10.1210/me.2004-0467
Source: PubMed


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
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    • "SNPs in the genes FKBP5, NR3C1, and CRHR1 have been selected for genotyping based on published positive association studies with depression or depressive symptoms for the respective SNPs and haplotypes (see Section 1). The SNPs with the strongest gene environment interaction effects, which mean depressive symptoms, were selected (CRHR1 SNPs: rs7209436 and rs110402 [28, 40]; NR3C1 SNPs: rs41423247, rs6195, and rs10482605 [42, 43]; FKBP5 SNPs: rs1360780, rs9296158, rs3800373, and rs9470080 [28, 46]). SNP IDs and their minor allele frequency (MAF) are reported in Table 1. "
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    • "The second variant results in arginine (R) to lysine(K) change. Presence of the ER22/23EK allele is related to the resistance to GC [21]. Additionally, C-reactive protein concentration [19] and changes in the balance between two isoforms of GR GRα ligand-dependent transcription factor and GRβ—having no transcriptional activity, was found to be related to the polymorphism [22, 23]. "
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