title: Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess.
abstract: 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.
authors.affiliation: Department of Nephrology and Hypertension, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland.
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.forename: Irena D
authors.initials: ID
authors.lastname: Ignatova
authors.forename: Lyubomir G
authors.initials: LG
authors.lastname: Nashev
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrari
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003348:Cortisone / Q000097:blood; D004795:Enzyme Stability; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000209:etiology*; D043204:Mineralocorticoid Excess Syndrome, Apparent / Q000209:etiology*; D009154:Mutation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003348:Cortisone; D006854:Hydrocortisone