Published Online
on July 14, 2003

A more recent version of this article appeared on August 1, 2003

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Submitted on March 14, 2003
Revised on April 17, 2003

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

Gareth G. Lavery; Vanessa Ronconi; Nicole Draper; Elizabeth H. Rabbitt; Val Lyons; Karen E. Chapman; Elizabeth A. Walker; Claire L. McTernan; Gilberta Giacchetti; Franco Mantero; Jonathan R. Seckl; Christopher R.W. Edwards; John M.C. Connell; Martin Hewison; and Paul M. Stewart^*

From the Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital (G.G.L., N.D., E.H.R., E.A.W., C.L.M., M.H., P.M.S.), Edgbaston, Birmingham, UK; the Division of Endocrinology, Department of Internal Medicine, University of Ancona (V.R., G.G.), Italy; Molecular Medicine, University of Edinburgh, Western General Hospital (V.L., K.E.C., J.R.S.), Edinburgh, UK; the Department of Medical and Surgical Sciences, University of Padova (F.M.), Italy; the Vice-Chancellor's Office, University of Newcastle-Upon-Tyne (C.R.W.E.), Newcastle-Upon-Tyne, UK; and the MRC Blood Pressure Group, Western Infirmary (J.M.C.C.), Glasgow, UK.

^* To whom correspondence should be addressed. E-mail: p.m.stewart{at}bham.ac.uk.

Abstract--Mutations in the gene encoding 11-hydroxysteroid dehydrogenase type 2, 11-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 11-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 <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from "essential" hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the HSD11B2 locus can have on blood pressure in later life.

Key words: hypertension, genetic • hypertension, essential • mutation • mineralocorticoids • genes

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