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

Evangelia Charmandari, Tomoshige Kino, Takamasa Ichijo, William Jubiz, Liliana Mejia, Keith Zachman, George P. Chrousos

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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 9α) 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 hGRαF737L 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 hGRα only after a short duration of exposure to the ligand. Conclusions: The mutant receptor hGRαF737L 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.

Original languageEnglish
Pages (from-to)3986-3990
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number10
DOIs
Publication statusPublished - Oct 2007
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Point Mutation
Glucocorticoids
Genes
Ligands
Nuclear Receptor Coactivator 2
Substitution reactions
Mouse mammary tumor virus
Signal transduction
Mineralocorticoids
Amino Acid Substitution
Phenylalanine
Viruses
Leucine
Carcinogens
Adrenocorticotropic Hormone
Dexamethasone
Hydrocortisone
Glucocorticoid Receptor Deficiency
Tumors

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. / Charmandari, Evangelia; Kino, Tomoshige; Ichijo, Takamasa; Jubiz, William; Mejia, Liliana; Zachman, Keith; Chrousos, George P.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 10, 10.2007, p. 3986-3990.

Research output: Contribution to journalArticle

Charmandari, Evangelia ; Kino, Tomoshige ; Ichijo, Takamasa ; Jubiz, William ; Mejia, Liliana ; Zachman, Keith ; Chrousos, George P. / A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 10. pp. 3986-3990.
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AU - Mejia, Liliana

AU - Zachman, Keith

AU - Chrousos, George P.

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