ObjectiveGeneralized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) geneNR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence ofNR3C1mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored.PatientsThe proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of anNR3C1mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied.ResultsA two-nucleotide deletion in exon 9α, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenicNR3C1mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels.ConclusionWe identified a novel frameshift mutation inNR3C1as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied byin vitroexperiments. Mutations inNR3C1do not seem to be common causes for hypertension with low renin and aldosterone levels.