Identification of Natural Human Glucocorticoid Receptor (hGR) Mutations or Polymorphisms and Their Functional Consequences at the HormoneReceptor Inte
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Glucocorticoids regulate a broad spectrum of physiologic functions essential for life and play an important role in the maintenance of basal and stress-related homeostasis. At the cellular level, the actions of glucocorticoids are mediated by the human glucocorticoid receptor α (hGRα), a ligand-dependent transcription factor ubiquitously expressed in almost all tissues and cells. The molecular mechanisms of hGRα action involve (a) binding to glucocorticoids, (b) cytoplasmic to nuclear translocation, (c) binding/association to DNA/chromatin, and (d) transcriptional activation or repression by interacting with cofactors and other transcription factors. Mutations or polymorphisms in the hGR gene may impair these molecular mechanisms of hGRα action, thereby altering tissue sensitivity to glucocorticoids. The latter may take the form of glucocorticoid resistance or glucocorticoid hypersensitivity and may be associated with significant morbidity. The identification of natural pathologic mutations in patients’ hGR gene and the subsequent examination of the functional defects of the natural mutant hGRα receptors would enhance our understanding of the molecular mechanisms of hGRα action and highlight the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.