Mutations in the 11β-Hydroxysteroid Dehydrogenase Type II Enzyme Associated with Hypertension and Possibly Stillbirth

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Abstract
The 11β-hydroxysteroid dehydrogenase type II enzyme (11ßHSD2) converts cortisol into cortisone, thus preventing occupation of the non-selective mineralocorticoid receptor by glucocorticoids in the kidney. Placental 11ßHSD2 is also thought to protect the fetus from the high maternal circulating levels of glucocorticoids. Mutations generating inactive enzymes have been described in the HSD11B2 gene in the congenital syndrome of apparent mineralocorticoid excess (AME) — a low renin form of hypertension. Recently, a mutation has been identified in a family with AME and in which there is a high incidence of stillbirths. In this study we have expressed the R374X mutation and show that the mutant is devoid of enzyme activity in intact mammalian cells expressing a significant level of the truncated protein. While this observation elucidates the cause of AME in this family the degree to which R374X also contributes to the higher incidence of failed pregnancies remains to be determined.