title: Late-onset apparent mineralocorticoid excess caused by novel compound heterozygous mutations in the HSD11B2 gene.
abstract: Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, 11beta-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 11beta-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.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ronconi
authors.forename: Nicole
authors.initials: N
authors.lastname: Draper
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Val
authors.initials: V
authors.lastname: Lyons
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walker
authors.forename: Claire L
authors.initials: CL
authors.lastname: McTernan
authors.forename: Gilberta
authors.initials: G
authors.lastname: Giacchetti
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Christopher R W
authors.initials: CR
authors.lastname: Edwards
authors.forename: John M C
authors.initials: JM
authors.lastname: Connell
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000293:Adolescent; D000328:Adult; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000175:diagnosis / Q000235:genetics*; D007008:Hypokalemia / Q000175:diagnosis; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D018076:DNA, Complementary; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human