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Review
. 2013;24:67-85.
doi: 10.1159/000342505. Epub 2013 Feb 1.

Primary Generalized Familial and Sporadic Glucocorticoid Resistance (Chrousos Syndrome) and Hypersensitivity

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Free PMC article
Review

Primary Generalized Familial and Sporadic Glucocorticoid Resistance (Chrousos Syndrome) and Hypersensitivity

Evangelia Charmandari et al. Endocr Dev. .
Free PMC article

Abstract

Familial or sporadic primary generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Primary generalized glucocorticoid hypersensitivity (PGGH) represents the mirror image of the former, and is characterized by generalized, partial, target-tissue hypersensitivity to glucocorticoids, and compensatory hypoactivation of the HPA axis. The molecular basis of both conditions has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair the molecular mechanisms of hGR action and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of Chrousos syndrome and PGGH.

Figures

Fig. 1
Fig. 1
a Schematic representation of the structure of the hGR gene. Alternative splicing of the primary transcript gives rise to the two mRNA and protein isoforms, hGRα and hGRβ. b Functional domains of the hGRα. The functional domains and subdomains are indicated beneath the linearized protein structures. NL = Nuclear localization.
Fig. 2
Fig. 2
Nucleocytoplasmic shuttling of the GR. Upon binding to the ligand, the activated hGRα dissociates from heat shock proteins (HSPs) and translocates into the nucleus, where it homodimerizes and binds to GREs in the promoter region of target genes or interacts with other transcription factors (TFs), such as activator protein-1, nuclear factor-κB and signal transducer and activator of transcription-5, ultimately modulating the transcriptional activity of respectively GRE- or TFRE-containing genes.
Fig. 3
Fig. 3
Location of the known mutations of the hGR gene causing Chrousos syndrome.
Fig. 4
Fig. 4
Arginine (R) to glutamine (Q) replacement at amino acid 714 of the hGRα alters 3-D structure of its LBD. a, b Arginine (R) to glutamine (Q) replacement at amino acid 714 of the hGRα causes formation of a new salt bridge between arginine (R) at 704 and aspartic acid (D) at 662. a In the wild-type hGRα LBD, R714 is tightly bound to D662 through an electrostatic salt bridge. b Substitution of arginine by glutamine in the hGRαR714Q LBD results in a rearrangement of the side chains, forming a new salt bridge between R704 and D662, while displacing Q714. This relaxes some constraint on helix 10 and results in structural changes throughout the LBD. c, d hGRαR714Q LBD has altered ligand-binding pocket. The ligand-binding pocket of the wild-type hGRα (c) and hGRαR714Q (d) are shown. Arginine to glutamine replacement at amino acid 714 causes alteration in the ligand-binding pocket in hGRαR714Q LBD. The greatest change observed between the wild-type hGRα LBD and hGRαR714Q LBD is in the rotameric state of Y735. e, f hGRαR714Q LBD has the destabilized AF-2 surface that blocks optimal binding of the LXXLL coactivator motif. The thickness and color of the Cα trace of the wild-type hGRα LBD (e) and hGRαR714Q LBD (f) indicate the areas of least (thin and blue) to most (thick and red) motion over the course of the simulation. As expected, the termini of the LBD and the bound peptide move the most. f There is significant motion at the mutation site (asterisk) in the mutant LBD, but not in the wildtype LBD, suggesting that the mutation causes destabilization in this structural area. The bound LXXLL peptide is, thus, more labile in the mutant LBD structure, as seen by the thickness of its Cα trace.
Fig. 5
Fig. 5
Schematic representation of the hGR gene polymorphisms located in the aminoterminal domain of the receptor and a summary of their clinical associations. CRP = C-reactive protein.

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