A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance

J Clin Endocrinol Metab. 2007 Oct;92(10):3986-90. doi: 10.1210/jc.2006-2830. Epub 2007 Jul 17.


Background: Generalized glucocorticoid resistance is a rare condition characterized by partial, end-organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/or mineralocorticoid activity. We have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor (hGR) gene and studied the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction.

Methods and results: We identified a novel, single, heterozygous nucleotide (T --> C) substitution at position 2209 (exon 9alpha) of the hGR gene, which resulted in phenylalanine (F) to leucine (L) substitution at amino acid position 737 within helix 11 of the ligand-binding domain of the protein. Compared with the wild-type receptor, the mutant receptor hGRalphaF737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone and displayed a 2-fold reduction in the affinity for ligand, a 12-fold delay in nuclear translocation, and an abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant-negative effect on the wild-type hGRalpha only after a short duration of exposure to the ligand.

Conclusions: The mutant receptor hGRalphaF737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation, and/or abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. These findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Binding Sites
  • COS Cells
  • Child
  • Chlorocebus aethiops
  • Endocrine System Diseases / genetics*
  • Endocrine System Diseases / metabolism
  • Glucocorticoids / metabolism*
  • Humans
  • Ligands
  • Male
  • Nuclear Receptor Coactivator 2 / metabolism
  • Point Mutation*
  • Protein Structure, Secondary
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism*
  • Signal Transduction / physiology
  • Transfection


  • Glucocorticoids
  • Ligands
  • Nuclear Receptor Coactivator 2
  • Receptors, Glucocorticoid