Apparent
mineralocorticoid excess (
AME) is a severe form of
hypertension that is caused by impaired activity of
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active
cortisol into inactive
cortisone. Mutations in HSD11B2 result in
cortisol-induced activation of
mineralocorticoid receptors and cause
hypertension with
hypokalemia, metabolic
alkalosis, and suppressed circulating
renin and
aldosterone concentrations. This study uncovered the first patient with
AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced
11beta-HSD2 activity. This study identified a cluster of
amino acids (335 to 339) in the C-terminus of
11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type
11beta-HSD2 is a relatively stable
enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones
glycerol and
dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type
11beta-HSD2 occurs through the
proteasome pathway. Therefore, impaired
11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of
hypertension in some individuals with
AME.