Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.
BACKGROUND
11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of hormonally active cortisol to inactive cortisone and is vital for dictating specificity for the mineralocorticoid receptor. Thus, in patients with congenital deficiency of 11 beta-HSD (the syndrome of apparent mineralocorticoid excess, AME), cortisol and not aldosterone acts as a mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of the renin-angiotensin-aldosterone axis. Two isoforms of human 11 beta-HSD have been described, but it is the NAD-dependent type 2 isoform (11 beta-HSD2), first characterised in placental tissue, that is expressed in the mineralocorticoid target tissues, kidney and colon. We have analysed the 11 beta-HSD2 gene as a candidate gene in explaining the molecular basis of AME.


METHODS
By exon-specific PCR-amplification of the 11 beta-HSD2 gene in a consanguineous kindred with AME, we found a point mutation (C1228T) in two affected siblings, and also in placental DNA obtained from a stillbirth pregnancy.


RESULTS
The mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at codon 374 instead of a normal arginine (R374X), with the deletion of 32 aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, who are phenotypically normal, are heterozygote for the C1228T mutation in keeping with an autosomal recessive form of inheritance. NAD-dependent 11 beta-HSD activity was severely attenuated in the stillbirth placenta compared with control placental tissue, and no 11 beta-HSD immunostaining was observed in this placenta with antisera derived against a C-terminal 11 beta-HSD2 peptide sequence.


CONCLUSIONS
AME is due to a mutation in the 11 beta-HSD2 gene, and is an example of human hypertension arising from a single gene defect.
Stewart
P M
PM
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, UK.
Krozowski
Z S
ZS
Gupta
A
A
Milford
D V
DV
Howie
A J
AJ
Sheppard
M C
MC
Whorwood
C B
CB
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics*; D006973:Hypertension / Q000209:etiology*; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics*; D008901:Mineralocorticoids / Q000097:blood; D008969:Molecular Sequence Data; D010920:Placenta / Q000737:chemistry; D017354:Point Mutation; D011247:Pregnancy; D013577:Syndrome
D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases