{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:21:21Z","timestamp":1791328881133,"version":"4.3.1"},"reference-count":35,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T00:00:00Z","timestamp":1436832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Natural mutations in the human glucocorticoid receptor (<jats:italic><jats:styled-content style=\"fixed-case\">hGR<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> NR<\/jats:styled-content>3C1<\/jats:italic>) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target\u2010tissue insensitivity to glucocorticoids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To present a new case of Chrousos syndrome caused by a novel mutation in the <jats:italic><jats:styled-content style=\"fixed-case\">hGR<\/jats:styled-content><\/jats:italic> gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design and Results<\/jats:title><jats: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\u00a0h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A\u00a0&gt;\u00a0G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A\u00a0&gt;\u00a0G, p.H726R). Compared with the wild\u2010type receptor, the mutant receptor <jats:styled-content style=\"fixed-case\">hGR<\/jats:styled-content>\u03b1H726R demonstrated decreased ability to transactivate glucocorticoid\u2010responsive genes and to transrepress the nuclear factor\u2010\u03baB signalling pathway, displayed 55% lower affinity for the ligand and a four\u2010fold delay in nuclear translocation, and interacted with the glucocorticoid receptor\u2010interacting protein 1 coactivator mostly through its activation function\u20101 domain. Finally, a 3\u2010dimensional 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The natural mutant receptor <jats:styled-content style=\"fixed-case\">hGR<\/jats:styled-content>\u03b1H726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.12470","type":"journal-article","created":{"date-parts":[[2015,5,29]],"date-time":"2015-05-29T19:05:30Z","timestamp":1432926330000},"page":"782-791","source":"Crossref","is-referenced-by-count":39,"title":["A novel mutation of the <i><scp>hGR<\/scp><\/i> gene causing Chrousos syndrome"],"prefix":"10.1111","volume":"45","author":[{"given":"Nicolas 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