HYPERTENSION IN THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS DUETO MUTATION OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2 GENE

Background 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse s the interconversion of hormonally active cortisol to inactive cortis one acid 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 aci d not aldosterone acts as a mineralocorticoid, resulting in hypertensi on and hypokalaemia with suppression of the renin-angiotensin-aldoster one axis. Two isoforms of human 11 beta-HSD have been described, but i t is the NAD-dependent type 2 isoform (11 beta-HSD2), first characteri sed in placental tissue, that is expressed in the mineralocorticoid ta rget 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 cons anguineous kindred with AME, we found a point mutation (C1228T) in two affected siblings, and also in placental DNA obtained from a stillbir th pregnancy. Findings The mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at codon 374 instead of a normal ar ginine (R374X), with the deletion of 32 aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, who are phenotypica lly normal, are heterozygote for the C1228T mutation in keeping with a n autosomal recessive form of inheritance. NAD-dependent 11 beta-HSD a ctivity was severely attenuated in the stillbirth placenta compared wi th control placental tissue, and no 11 beta-HSD immunostaining was obs erved in this placenta with antisera derived against a C-terminal 11 b eta-HSD2 peptide sequence. Interpretation 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.