Decreased Deoxyribonucleic Acid Binding of Glucocorticoid-Receptor Complex in Cultured Skin Fibroblasts from a Patient with the Glucocorticoid Resistance Syndrome*

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Abstract
A patient with the syndrome of glucocorticoid resistance was studied. A 27-yr-old woman initially was diagnosed as having Cushing's disease, based on the findings of high plasma ACTH and serum cortisol levels, increased urinary cortisol secretion, resistance to adrenal suppression with dexamethasone, and bilateral adrenal hyperplasia by computed tomography and scintigraphy of the adrenal glands. However, she had no signs or symptoms of Cushing's syndrome. During a 5-yr follow-up, no clinical abnormalities developed, although hypercortisolism persisted. End-organ resistance to cortisol was suspected. To explain the end-organ resistance to cortisol, the glucocorticoid receptors (GR) in peripheral mononuclear leukocytes and cultured skin fibroblasts from a forearm skin biopsy were characterized and compared with the results of similar studies in normal subjects. The patient's GR in whole cell assays had an increased dissociation constant (Kd). In the cytosol of cultured skin fibroblasts from the patient, there was also decreased binding capacity. The thermal stability and the sedimentation coefficient in a sucrose density gradient of the receptors in the cytosol of cultured skin fibroblasts from the patient and normal subjects were similar. GR complex activation, analyzed by DEAE-cellulose chromatography, was decreased in the patient. DNA binding of the GR complex after temperature-induced activation was lower in the patient than in normal subjects. Nuclear translocation of GR complexes from the patient was also slightly decreased. These results suggest that the patient's glucocorticoid resistance was due to a decrease in the affinity of the receptor for glucocorticoids and a decrease in the binding of the GR complex to DNA.