Elsevier

The Lancet

Volume 347, Issue 8994, 13 January 1996, Pages 88-91
The Lancet

Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene

https://doi.org/10.1016/S0140-6736(96)90211-1Get rights and content

Abstract

Summary

Background 11β-hydroxysteroid dehydrogenase (11β-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 11β-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 11β-HSD have been described, but it is the NAD-dependent type 2 isoform (11β-HSD2), first characterised in placental tissue, that is expressed in the mineralocorticoid target tissues, kidney and colon. We have analysed the 11β-HSD2gene as a candidate gene in explaining the molecular basis of AME.

Methods By exon-specific PCR-amplification of the 11β-HSD2gene 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.

Findings The mutation in exon 5 of the 11β-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 11β-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 11β-HSD activity was severely attenuated in the stillbirth placenta compared with control placental tissue, and no 11β-HSD immunostaining was observed in this placenta with antisera derived against a C-terminal 11β-HSD2 peptide sequence.

Interpretation AME is due to a mutation in the 11β-HSD2gene, and is an example of human hypertension arising from a single gene defect.

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