title: A novel mutation of the hGR gene causing Chrousos syndrome.
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.
  
  
  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.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital, University of Athens Medical School, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Nicolaides
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Icahn School of Medicine at Mount Sinai School, New York, NY, USA.
authors.forename: Eliza B
authors.initials: EB
authors.lastname: Geer
authors.affiliation: Bioinformatics and Medical Informatics Team, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Vlachakis
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital, University of Athens Medical School, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
authors.forename: Anna-Maria G
authors.initials: AM
authors.lastname: Psarra
authors.affiliation: Department of Clinical Biochemistry, 'Attiko' Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Moutsatsou
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital, University of Athens Medical School, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.affiliation: Bioinformatics and Medical Informatics Team, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.|IMGT®, The International ImMunoGeneTics Information System®, Institute of Human Genetics, Montpellier, France.
authors.forename: Sophia
authors.initials: S
authors.lastname: Kossida
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, 'Aghia Sophia' Children's Hospital, University of Athens Medical School, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
mesh_terms: D000152:Acne Vulgaris / Q000235:genetics; D000328:Adult; D000505:Alopecia / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000235:genetics; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D005221:Fatigue / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006628:Hirsutism / Q000235:genetics; D006801:Humans; D008599:Menstruation Disturbances / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics; D013577:Syndrome
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid
keywords: Chrousos syndrome; glucocorticoid receptor; glucocorticoid signalling; mutations