Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene

ABSTRACT—Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in...

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Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2003-08, Vol.42 (2), p.123-129
Main Authors: Lavery, Gareth G, Ronconi, Vanessa, Draper, Nicole, Rabbitt, Elizabeth H, Lyons, Val, Chapman, Karen E, Walker, Elizabeth A, McTernan, Claire L, Giacchetti, Gilberta, Mantero, Franco, Seckl, Jonathan R, Edwards, Christopher R.W, Connell, John M.C, Hewison, Martin, Stewart, Paul M
Format: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenase Type 2
Adolescent
Adult
Arterial hypertension. Arterial hypotension
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cell Line
Clinical manifestations. Epidemiology. Investigative techniques. Etiology
DNA, Complementary - metabolism
Female
Gene Expression
Genetic Predisposition to Disease
Heterozygote
Humans
Hydroxysteroid Dehydrogenases - genetics
Hydroxysteroid Dehydrogenases - metabolism
Hypertension - diagnosis
Hypertension - genetics
Hypokalemia - diagnosis
Male
Medical sciences
Mineralocorticoids - metabolism
Mutation
Pedigree
Phenotype
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Summary:ABSTRACT—Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all
ISSN:0194-911X
1524-4563
DOI:10.1161/01.HYP.0000083340.57063.35