Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder

Abstract

Context: Primary generalized glucocorticoid resistance is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. We review the clinical aspects, molecular mechanisms, and implications of this disorder.

Evidence acquisition: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through February 2008) to identify original articles and reviews on this topic.

Evidence synthesis: We have relied on the experience of a number of experts in the field, including our extensive personal experience.

Conclusions: The clinical spectrum of primary generalized glucocorticoid resistance is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.

Figure 1

A, Nucleocytoplasmic shuttling of the GR. Upon binding to the ligand, the activated hGRα dissociates from HSPs and translocates into the nucleus, where it homodimerizes and binds to GREs in the promoter region of target genes. B, Schematic representation of the interaction of AF-1 and AF-2 of hGRα with coactivators. p/CAF, p300/CBP-associated factor; SWI/SNF, switching/sucrose nonfermenting; TF, transcription factor; TFRE, transcription factor response element.

Figure 2

A, Alterations in the HPA axis in generalized glucocorticoid resistance. The impaired glucocorticoid feedback inhibition at the hypothalamic and anterior pituitary levels results in increased secretion of CRH and ACTH, adrenal hyperplasia, and increased secretion of adrenal steroids with mineralocorticoid and/or androgenic activity. B, Location of the known mutations of the hGR gene (upper panel) and protein (lower panel). C, Crystal structure of the LBD of the hGRα. Stereotactic conformation of the agonist (left) and antagonist (right) form of the LBD of hGRα. The yellow arrows indicate the position of H12, which is critical for the formation of the AF-2 surface that allows interaction with activators. D, Location of the known mutations of hGRα in the agonist (upper panel) and antagonist (lower panel) form of the LBD of hGRα. Helices are indicated in red and are underlined, whereas β-sheets are indicated in green. Two mutations (I559 and V571A) are located within H5, whereas four mutations (V729I, F737L, I747M, and L773P) are located within or close to helices 11 and 12. The ligand-binding pocket is formed by helices 3, 5, 11, and 12. Upon ligand binding, the receptor undergoes major conformational changes that alter the position of H11 and H12, and generate an interaction surface that allows coactivators to bind to the LBD through their LXXLL motifs. H12 plays a critical role in the formation of both the ligand-binding pocket and the AF-2 surface that facilitates interaction with coactivators. The fact that most hGRα mutations are clustered around H5, H11, and H12 indicates that these helices play an important role in glucocorticoid signal transduction. AVP, Arginine vasopressin; NTD, amino terminal domain.

Figure 2C

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