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Eur J Clin Invest. 2015 Aug;45(8):782-91. doi: 10.1111/eci.12470. Epub 2015 Jul 14.

A novel mutation of the hGR gene causing Chrousos syndrome.

Author information

1
Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital, University of Athens Medical School, Athens, Greece.
2
Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
3
Division of Endocrinology, Diabetes, and Bone Diseases, Icahn School of Medicine at Mount Sinai School, New York, NY, USA.
4
Bioinformatics and Medical Informatics Team, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
5
Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
6
Department of Clinical Biochemistry, 'Attiko' Hospital, University of Athens Medical School, Athens, Greece.
7
IMGT®, The International ImMunoGeneTics Information System®, Institute of Human Genetics, Montpellier, France.

Abstract

BACKGROUND:

Natural mutations in the human glucocorticoid receptor (hGR, NR3C1) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids.

OBJECTIVE:

To present a new case of Chrousos syndrome caused by a novel mutation in the hGR gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction.

DESIGN AND RESULTS:

The index case presented with hirsutism, acne, alopecia, anxiety, fatigue and irregular menstrual cycles, but no clinical manifestations suggestive of Cushing's syndrome. Endocrinologic evaluation revealed elevated 08:00 h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A > G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A > G, p.H726R). Compared with the wild-type receptor, the mutant receptor hGRαH726R demonstrated decreased ability to transactivate glucocorticoid-responsive genes and to transrepress the nuclear factor-κB signalling pathway, displayed 55% lower affinity for the ligand and a four-fold delay in nuclear translocation, and interacted with the glucocorticoid receptor-interacting protein 1 coactivator mostly through its activation function-1 domain. Finally, a 3-dimensional molecular modelling study of the H726R mutation revealed a significant structural shift in the rigidity of helix 10 of the receptor, which resulted in reduced flexibility and decreased affinity of the mutant receptor for binding to the ligand.

CONCLUSIONS:

The natural mutant receptor hGRαH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids.

KEYWORDS:

Chrousos syndrome; glucocorticoid receptor; glucocorticoid signalling; mutations

PMID:
26031419
DOI:
10.1111/eci.12470
[Indexed for MEDLINE]

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