A Novel Mutation of the hGR Gene Causing Chrousos Syndrome

Eur J Clin Invest. 2015 Aug;45(8):782-91. doi: 10.1111/eci.12470. Epub 2015 Jul 14.

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 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 08:00 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.

Keywords: Chrousos syndrome; glucocorticoid receptor; glucocorticoid signalling; mutations.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acne Vulgaris / genetics
  • Adult
  • Alopecia / genetics
  • Animals
  • Anxiety / genetics
  • Blotting, Western
  • COS Cells
  • Chlorocebus aethiops
  • Fatigue / genetics
  • Female
  • Gene Expression Regulation
  • Genotype
  • Hirsutism / genetics
  • Humans
  • Menstruation Disturbances / genetics
  • Metabolism, Inborn Errors / genetics*
  • Models, Molecular
  • Molecular Docking Simulation
  • Mutation
  • Receptors, Glucocorticoid / deficiency*
  • Receptors, Glucocorticoid / genetics
  • Syndrome

Substances

  • NR3C1 protein, human
  • Receptors, Glucocorticoid

Supplementary concepts

  • Glucocorticoid Receptor Deficiency