Functional characterization of the hGRαT556I causing Chrousos syndrome. (15th December 2015)

• Record Type: Journal Article
• Authors: Nicolaides, Nicolas C.; Skyrla, Eirini; Vlachakis, Dimitrios; Psarra, Anna‐Maria G.; Moutsatsou, Paraskevi; Sertedaki, Amalia; Kossida, Sophia; Charmandari, Evangelia
• Is Part Of: European journal of clinical investigation. Volume 46:Number 1(2016:Jan.)
• Page Start: 42
• Page End: 49
• Publication Date: 2015-12-15
• Subjects: Chrousos syndrome -- glucocorticoid receptor -- glucocorticoid signalling -- hGR mutations; Pathology -- Periodicals; Medical research -- Periodicals; 616.075
• DOI: 10.1111/eci.12563
• Languages: English
• ISSNs: 0014-2972

Abstract

Abstract: Background: Chrousos syndrome is a rare pathologic condition characterized by generalized, partial resistance of target tissues to glucocorticoids and caused by inactivating mutations of the human glucocorticoid receptor ( hGR ) gene. A novel case of Chrousos syndrome has been reported in a patient with adrenal incidentaloma, who harboured a heterozygous point mutation in the hGR gene, which resulted in threonine (T) to isoleucine (I) substitution at amino acid position 556 in the ligand‐binding domain of the receptor. Objective: To delineate the molecular mechanisms through which the mutant receptor hGRαT556I causes Chrousos syndrome. Design and Results: Compared with the wild‐type receptor, the mutant receptor hGRαT556I demonstrated 50% reduction in its ability to transactivate glucocorticoid‐responsive genes and in the affinity for the ligand, 30% increase in the ability to transrepress the nuclear factor‐κB‐target genes and a 3, 4‐fold delay in the cytoplasmic‐to‐nuclear translocation. The mutant receptor hGRαT556I did not exert a dominant negative effect upon the hGRα‐mediated transcriptional activity; it preserved its ability to bind to DNA and interacted with the glucocorticoid receptor‐interacting protein 1 coactivator mostly through its activation function‐1 domain. Structural biology studies revealed that the T556I mutation caused disruption of the hydrogen bond formed by the T556 with the =O group of P637 backbone, which resulted in a significant relocation of the P637‐bearing loop. This conformational alteration affected the local 3D arrangement of the receptor and hence the electrostatic surface of the region. Conclusions: The hGRαT556I causes Chrousos syndrome by impairing multiple steps of the glucocorticoid signal transduction pathway.