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Natural Glucocorticoid Receptor Mutants Causing Generalized Glucocorticoid Resistance: Molecular Genotype, Genetic Transmission, and Clinical Phenotype

Pediatric and Reproductive Endocrinology Branch (E.C., T.K., E.S., A.V., G.P.C.), National Institute of Child Health and Human Development, and Diabetes Branch (N.B.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Evangelia Charmandari, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583.

Glucocorticoid resistance is a rare, familial, or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition ranges from completely asymptomatic to severe hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance in several families and sporadic cases has been ascribed to mutations in the human glucocorticoid receptor- (hGR) gene, which impair the ability of the receptor to transduce the glucocorticoid signal. We systematically investigated the molecular mechanisms through which natural, ligand-binding domain hGR mutants, including hGRI559N, hGRV571A, hGRD641V, hGRV729I, and hGRI747M, produce a defective signal and determined whether their differential effects on hGR function might account for the type of genetic transmission of the disorder and the variable clinical phenotype of the affected subjects. Our findings suggest that all five mutant receptors studied have ligand-binding domains with decreased intrinsic transcriptional activity. Unlike hGRI559N and I747M previously shown to exert a dominant negative effect upon the transcriptional activity of hGR, hGRV571A, D641V, and V729I do not have such an effect. All five mutants studied demonstrate varying degrees of decreased affinity for the ligand in a standard dexamethasone binding assay, but preserve their ability to bind DNA. The nondominant negative mutants, hGRV571A, D641V, and V729I, show delayed translocation into the nucleus after exposure to ligand. Finally, hGRI559N, V571A, D641V, and V729I display an abnormal interaction with the glucocorticoid receptor-interacting protein-1 coactivator in vitro, as this was previously shown also for hGRI747M. We conclude that each of the above hGR mutations imparts different functional defects upon the glucocorticoid signal transduction pathway, which explains the autosomal recessive or dominant transmission of the disorder, but might only explain in part its variable clinical phenotype.

Abbreviations: AF, Activation function; CBP, cAMP response element-binding protein-binding protein; DBD, DNA-binding domain; FBS, fetal bovine serum; GFP, green fluorescent protein; GR, glucocorticoid receptor; GRE, glucocorticoid-response element; GRIP, GR-interacting protein 1; GST, glutathione-S-transferase; hGR, human glucocorticoid receptor-; hsp90, 90-kDa heat shock protein; LBD, ligand-binding domain; MMTV, mouse mammary tumor virus; NLS, nuclear localization signal; NRB, nuclear receptor-binding; RSV, Rous sarcoma virus; SV40, simian virus 40.

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