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A Novel Point Mutation in the Amino Terminal Domain of the Human Glucocorticoid Receptor (hGR) Gene Enhancing hGR-Mediated Gene Expression

Division of Endocrinology and Metabolism (E.C., G.P.C.), Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Section on Pediatric Endocrinology (E.C., T.I., S.B., K.Z., G.P.C., T.K.), Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Centro de Endocrinologia (W.J.), Cali, Colombia

Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens 11527, Greece. E-mail: evangelia.charmandari{at}googlemail.com.

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 hGR. We investigated the molecular mechanisms of action of the natural mutant receptor hGRD401H.

Methods-Results: Compared with the wild-type hGR, the mutant receptor hGRD401H 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 hGRD401H 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 hGRD401H 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.