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(Hypertension. 1999;34:638-642.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Mutants of 11ß-Hydroxysteroid Dehydrogenase (11-HSD2) With Partial Activity

Improved Correlations Between Genotype and Biochemical Phenotype in Apparent Mineralocorticoid Excess

B. Scott Nunez; Fraser M. Rogerson; Tomoatsu Mune; Yoshio Igarashi; Yuichi Nakagawa; George Phillipov; Asha Moudgil; Luther B. Travis; Mario Palermo; Cedric Shackleton; Perrin C. White

From the Department of Pediatrics, University of Texas Southwestern Medical Center (B.S.N., F.M.R., P.C.W.), Dallas, Tex; Prince Henry's Institute of Medical Research (F.M.R.), Clayton, Victoria, Australia; Third Department of Internal Medicine, Gifu University School of Medicine (T.M.), Gifu, Japan; Department of Pediatrics, Hamamatsu University School of Medicine (Y.I., Y.N.), Hamamatsu, Japan; Queen Elizabeth Hospital (G.P.), Woodville, South Australia, Australia; Division of Pediatric Nephrology, Cedars-Sinai Medical Center (A.M.), Los Angeles, Calif; Department of Pediatrics, University of Texas Medical Branch (L.B.T.), Galveston, Tex; and the Children's Hospital Oakland Research Institute (M.P., C.S.), Oakland, Calif.

Correspondence to Perrin C. White, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9063. E-mail pwhit2{at}mednet.swmed.edu

Abstract—Mutations in the kidney isozyme of human 11-hydroxysteroid dehydrogenase (11-HSD2) cause apparent mineralocorticoid excess, an autosomal recessive form of familial hypertension. We studied 4 patients with AME, identifying 4 novel and 3 previously reported mutations in the HSD11B2 (HSD11K) gene. Point mutations causing amino acid substitutions were introduced into a pCMV5/11HSD2 expression construct and expressed in mammalian CHOP cells. Mutations L179R and R208H abolished activity in whole cells. Mutants S180F, A237V, and A328V had 19%, 72%, and 25%, respectively, of the activity of the wild-type enzyme in whole cells when cortisol was used as the substrate and 80%, 140%, and 55%, respectively, of wild-type activity when corticosterone was used as the substrate. However, these mutant proteins were only 0.6% to 5.7% as active as the wild-type enzyme in cell lysates, suggesting that these mutations alter stability of the enzyme. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, demonstrated in whole cells, when cortisol was used as the substrate. These included the ratio of urinary cortisone to cortisol metabolites (R²=0.648, P<0.0001), age at presentation (R²=0.614, P<0.0001), and birth weight (R²=0.576, P=0.0004). Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1.

Key Words: hydroxysteroid dehydrogenases • hypertension • hydrocortisone • metabolism • mutation • mineralocorticoids

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