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(Hypertension. 1999;34:435-441.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Genetic, Biochemical, and Clinical Studies of Patients With A328V or R213C Mutations in 11ßHSD2 Causing Apparent Mineralocorticoid Excess

Gilles Morineau; Jean-Michel Marc; Ahmed Boudi; Herve Galons; Micheline Gourmelen; Pierre Corvol; Leigh Pascoe; Jean Fiet

From Biologie Hormonale (G.M., J.F.), Hôpital Saint-Louis, France; Néphrologie, CHG (J.-M.M.), Annonay, France; Chimie Organique, Faculté de Pharmacie (A.B., H.G.), Paris, France; Service d'Explorations Fonctionnelles (M.G.), Hôpital Trousseau, Paris, France; Inserm U36 (P.C.), Collège de France, Paris, France; Fondation Jean Dausset CEPH (L.P.), Paris, France; and Biochimie, Faculté de Pharmacie (J.F.), Paris, France.

Abstract—Apparent mineralocorticoid excess is a recessively inherited hypertensive syndrome caused by mutations in the 11ß-hydroxysteroid dehydrogenase type 2 gene, which encodes the enzyme normally responsible for converting cortisol to inactive cortisone. Failure to convert cortisol to cortisone in mineralocorticoid-sensitive tissues permits cortisol to bind to and activate mineralocorticoid receptors, causing hypervolemic hypertension. Typically, these patients have increased ratios of cortisol to cortisone and of 5- to 5ß-cortisol metabolites in serum and urine. We have studied 3 patients in 2 families with severe, apparent mineralocorticoid excess and other family members in terms of their genetic, biochemical, and clinical parameters, as well as normal controls. Two brothers were homozygous for an A328V mutation and the third patient was homozygous for an R213C mutation in the 11ß-hydroxysteroid dehydrogenase type 2 gene; both mutations caused a marked reduction in the activity of the encoded enzymes in transfection assays. The steroid profiles of the 7 heterozygotes and 2 other family members studied were completely normal. The results of a novel assay used to distinguish 5- and 5ß-tetrahydrometabolites suggest that 5ß-reductase activity is reduced or inhibited in apparent mineralocorticoid excess. In 1 patient undergoing renal dialysis for chronic renal insufficiency, direct control of salt and water balance completely corrected the hypertension, emphasizing the importance of mineralocorticoid action in this syndrome.

Key Words: hydroxysteroid • tetrahydrocortisone • hemodialysis • mutation • hypertension, genetic

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