Format

Send to

Choose Destination
Eur J Clin Invest. 2016 Jan;46(1):42-9. doi: 10.1111/eci.12563. Epub 2015 Dec 15.

Functional characterization of the hGRαT556I causing Chrousos syndrome.

Author information

1
Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.
2
Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
3
Bioinformatics and Medical Informatics Team, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
4
Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
5
Department of Clinical Biochemistry, University of Athens Medical School, 'Attiko' Hospital, Athens, Greece.
6
IMGT®, The International ImMunoGeneTics Information System®, Institute of Human Genetics, Montpellier, France.

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.

KEYWORDS:

Chrousos syndrome; glucocorticoid receptor; glucocorticoid signalling; hGR mutations

PMID:
26541474
DOI:
10.1111/eci.12563
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center