Late-onset apparent mineralocorticoid excess caused by novel compound heterozygous mutations in the HSD11B2 gene.
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.
Lavery
Gareth G
GG
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Ronconi
Vanessa
V
Draper
Nicole
N
Rabbitt
Elizabeth H
EH
Lyons
Val
V
Chapman
Karen E
KE
Walker
Elizabeth A
EA
McTernan
Claire L
CL
Giacchetti
Gilberta
G
Mantero
Franco
F
Seckl
Jonathan R
JR
Edwards
Christopher R W
CR
Connell
John M C
JM
Hewison
Martin
M
Stewart
Paul M
PM
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
D018076:DNA, Complementary; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human