A novel mutation of the hGR gene causing Chrousos syndrome.
Eur J Clin Invest
; 45(8): 782-91, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-26031419
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 ANDRESULTS:
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 0800 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Glucocorticoides
/
Erros Inatos do Metabolismo
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Eur J Clin Invest
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Grécia