title: A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.
abstract: BACKGROUND
  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 hGRalpha. We investigated the molecular mechanisms of action of the natural mutant receptor hGRalphaD401H.
  
  
  RESULTS
  Compared with the wild-type hGRalpha, the mutant receptor hGRalphaD401H 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 hGRalphaD401H 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 hGRalphaD401H 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.
authors.affiliation: Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens 11527, Greece. evangelia.charmandari@googlemail.com
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ichijo
authors.forename: William
authors.initials: W
authors.lastname: Jubiz
authors.forename: Smita
authors.initials: S
authors.lastname: Baid
authors.forename: Keith
authors.initials: K
authors.lastname: Zachman
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D003907:Dexamethasone / Q000378:metabolism; D005091:Exons / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D017354:Point Mutation / Q000235:genetics* / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; C491310:GRIP1 protein, human; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D005982:Glutathione Transferase