title: Molecular analysis of 11 beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess.
abstract: The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11 beta-hydroxysteroid dehydrogenase (11-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. The deficiency allows mineralocorticoid receptors to be occupied by cortisol, because these receptors themselves have similar affinities for cortisol and aldosterone. There are two isozymes of 11-HSD, a liver (L) or type 1 isozyme with a relatively low affinity for steroids, and a kidney (K) or type 2 isozyme with high steroid affinity. Mutations in the gene for the kidney isozyme of 11-HSD have been detected in all kindreds with AME. We expressed enzymes carrying all known missense mutations in cultured cells and determined their activity. For each patient with AME, we compared the enzymatic activity predicted by the genotype with the ratio of cortisol to cortisone metabolites in the urine, (THF + aTHF)/THE. These were strongly correlated, suggesting that the biochemical phenotype of AME is largely determined by genotype. The K isozyme of 11-HSD is also expressed in high levels in the placenta, where its function is unclear. AME patients often have low birth weight. By analogy with AME, low placental 11-HSD K activity in humans might be a risk factor for low birth weight and subsequent hypertension. However, we found that there was no significant correlation between 11-HSD activity, mRNA levels, and either fetal or placental weight.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: White
authors.forename: T
authors.initials: T
authors.lastname: Mune
authors.forename: F M
authors.initials: FM
authors.lastname: Rogerson
authors.forename: K M
authors.initials: KM
authors.lastname: Kayes
authors.forename: A K
authors.initials: AK
authors.lastname: Agarwal
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000483:Alleles; D000818:Animals; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008901:Mineralocorticoids / Q000378:metabolism*; D009154:Mutation; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D013577:Syndrome; D014158:Transcription, Genetic
chemical_list: D018076:DNA, Complementary; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases