A novel mutation of the hGR gene causing Chrousos syndrome. (14th July 2015)

• Record Type: Journal Article
• Authors: Nicolaides, Nicolas C.; Geer, Eliza B.; Vlachakis, Dimitrios; Roberts, Michael L.; Psarra, Anna‐Maria G.; Moutsatsou, Paraskevi; Sertedaki, Amalia; Kossida, Sophia; Charmandari, Evangelia
• Is Part Of: European journal of clinical investigation. Volume 45:Number 8(2015:Aug.)
• Page Start: 782
• Page End: 791
• Publication Date: 2015-07-14
• Subjects: Pathology -- Periodicals; Medical research -- Periodicals; 616.075
• DOI: 10.1111/eci.12470
• Languages: English
• ISSNs: 0014-2972

Abstract

<abstract abstract-type="main" id="eci12470-abs-0001"> <title>Abstract</title> <sec id="eci12470-sec-0001" sec-type="section"> <title>Background</title> <p>Natural mutations in the human glucocorticoid receptor (<italic>hGR, NR3C1</italic>) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target‐tissue insensitivity to glucocorticoids.</p> </sec> <sec id="eci12470-sec-0002" sec-type="section"> <title>Objective</title> <p>To present a new case of Chrousos syndrome caused by a novel mutation in the <italic>hGR</italic> gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction.</p> </sec> <sec id="eci12470-sec-0003" sec-type="section"> <title>Design and Results</title> <p>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.</p> </sec> <sec id="eci12470-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The natural mutant receptor hGRαH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids.</p> </sec> </abstract>