Endocrine Abstracts (2002) 3 OC4

Analysis of novel mutations in the HSD11B2 gene: Implications for AME and possibly IUGR

GG Lavery1, V Ronconi2, N Draper1, SM Chalder1, EA Walker1, CL Mcternan1, F Mantero2, M Hewison1 & PM Stewart1

1Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK; 2Division of Endocrinology, University of Ancona, Ospedale Regionale di Torrette, Ancona, Italy.

Mutations in the HSD11B2 gene explain the syndrome of apparent mineralocorticoid excess (AME), which is characterised by severe hypokalemic hypertension. The enzyme product of the HSD11B2 gene, 11-beta hydroxysteroid dehydrogenase type 2 (11beta HSD2), converts cortisol to its inactive form, cortisone. This reaction occurs primarily in the kidney, preventing the mineralocorticoid effects of cortisol, and in the placenta where it is believed to regulate fetal growth by protecting the fetus from maternal glucocorticoids. Here we describe 6 novel HSD11B2 mutations found in 2 compound heterozygotes and 1 heterozygote with AME and present data on sequencing the HSD11B2 gene in 25 family trios affected with IUGR and 146 adult controls. Mutations Y226N, L359W and L376P all abolish enzyme activity as inferred by enzyme assays using transfected mutant cDNAs. Two other mutations appear to affect correct splicing of the HSD11B2 pre-mRNA transcript and are being investigated using mini-gene constructs and mRNA analysis in transfected cells. The first splicing mutation is a G-A transition at the first position of intron 3 and is predicted to destroy the donor splice site signal. The second splicing mutation is silent, is found in exon 4 (val254/Val C771G) and predicts a cryptic donor splice site splice site 5' of the authentic site. The final mutation, C1393T, is in the 3' untranslated region that may alter 11betaHSD2 mRNA stability. The C1393T mutation was discovered in the AME kindred already affected with Y226N and Val254/Val mutations and has not previously been reported. Whilst mutations within the coding region of the HSD11B2 gene were not previously observed in placentae from IUGR babies, 20% of mothers from trios carried the C1393T mutation. To date C1393T has not been observed in 146 multi ethnic adult controls. These naturally occurring mutations provide insight into the pathogenesis of hypertension, and possibly fetal growth.

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