Regulation of glucocorticoid receptor gamma (GRgamma) by glucocorticoid receptor haplotype and glucocorticoid.
Stevens A., Donn R., Ray D.
OBJECTIVE: To measure glucocorticoid receptor gamma (GRgamma) expression in transformed lymphocytes from individuals of known GR gene haplotype. Recently, a glucocorticoid receptor haplotype (GAT) has been described that associates with increased sensitivity to dexamethasone. As there is strong linkage disequilibrium across the gene, this haplotype is likely to extend through exon 3, altered splicing of which generates the GRgamma isoform, a splice variant with impaired transactivation activity. Therefore we proposed that the GR haplotype affects glucocorticoid sensitivity either by influencing GRgamma expression basally, or in response to Gc exposure. DESIGN: We have measured expression of GRgamma, using a validated RT-PCR assay in human B lymphoblast cells of known haplotype under basal conditions, and after dexamethasone treatment. PATIENTS: The A549 human lung cell line and normal volunteers, five with the GAT GR haplotype and three with the CGA haplotype. MEASUREMENTS: Relative expression of GRgamma compared to total GR mRNA. RESULTS: GRgamma made up 5-6% of all the GR transcripts. There was no effect of carriage of the GR gene GAT haplotype on this expression. There was no effect of dexamethasone on relative expression of GRgamma. CONCLUSIONS: We propose that the GRgamma isoform is a product of constitutive splicing, that it does not explain the GR haplotype association with altered glucocorticoid sensitivity, and is unlikely to play an important physiological role in affecting glucocorticoid sensitivity. As glucocorticoids do not affect GRgamma expression, relative to total GR, this splice variant is unlikely to influence glucocorticoid treatment response.