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A novel mutation of the hGR gene causing Chrousos syndrome
Nicolaides, Nicolas C.
Geer, Eliza B.
Vlachakis, Dimitrios and
Roberts, Michael L.
Psarra, Anna-Maria G.
Moutsatsou, Paraskevi
and Sertedaki, Amalia
Kossida, Sophia
Charmandari, Evangelia
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 08:00h 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
hGRH726R demonstrated decreased ability to transactivate
glucocorticoid-responsive genes and to transrepress the nuclear factor-B
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 hGRH726R impairs multiple steps
of glucocorticoid signal transduction, thereby decreasing tissue
sensitivity to glucocorticoids.
(EN)
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