A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression

Evangelia Charmandari, Takamasa Ichijo, William Jubiz, Smita Baid, Keith Zachman, George P. Chrousos, Tomoshige Kino

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Context: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G → C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRα. We investigated the molecular mechanisms of action of the natural mutant receptor hGRαD401H. Methods-Results: Compared with the wild-type hGRα, the mutant receptor hGRαD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 ± 0.6 vs. 6.1 ± 0.6 nM) and time to nuclear translocation (14.75 ± 0.25 vs. 14.25 ± 1.13 min). The mutant receptor hGRαD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. Conclusions: The mutant receptor hGRαD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome.

Original languageEnglish
Pages (from-to)4963-4968
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number12
DOIs
Publication statusPublished - Dec 2008
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Point Mutation
Gene expression
Glucocorticoids
Genes
Gene Expression
Nuclear Receptor Coactivator 2
Substitution reactions
Mouse mammary tumor virus
Response Elements
Amino Acid Substitution
Polymorphism
Viruses
Histidine
Aspartic Acid
Carcinogens
Dexamethasone
Hydrocortisone
Tumors
Exons

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression. / Charmandari, Evangelia; Ichijo, Takamasa; Jubiz, William; Baid, Smita; Zachman, Keith; Chrousos, George P.; Kino, Tomoshige.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 12, 12.2008, p. 4963-4968.

Research output: Contribution to journalArticle

Charmandari, Evangelia ; Ichijo, Takamasa ; Jubiz, William ; Baid, Smita ; Zachman, Keith ; Chrousos, George P. ; Kino, Tomoshige. / A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 12. pp. 4963-4968.
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