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A Mutation in the Cofactor-Binding Domain of 11ß-Hydroxysteroid Dehydrogenase Type 2 Associated with Mineralocorticoid Hypertension¹

Division of Nephrology and Hypertension, Inselspital, University of Berne (A.O., B.D., P.A., T.Z., V.P., B.M.F., F.J.F., P.F.), 3010 Berne, Switzerland; and Pediatric Service, Hospital Nacional Prof. A. Posadas (M.N.D., H.R.), Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Paolo Ferrari, M.D., Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland. E-mail: paolo.ferrari{at}insel.ch

Renal 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) is an enzyme responsible for the peripheral inactivation of cortisol to cortisone in mineralocorticoid target tissues. Mutations in the gene encoding 11ßHSD2 cause the syndrome of apparent mineralocorticoid excess (AME), an autosomal recessive form of inherited hypertension, in which cortisol acts as a potent mineralocorticoid. The mutations reported to date have been confined to exons 3–5.

Here, we describe two siblings, 1 and 2 yr old, who were diagnosed with hypokalemic hypertension and low plasma aldosterone and renin levels, indicating mineralocorticoid hypertension. Analysis of urinary steroid metabolites showed a markedly impaired metabolism of cortisol, with (tetrahydrocortisol + 5-tetrahydrocortisol)/tetrahydrocortisone ratios of 40–60, and nearly absent urinary free cortisone. Although phenotypically normal, the heterozygous parents showed a disturbed cortisol metabolism.

Genetic analysis of the HSD11B2 gene from the AME patients revealed the homozygous deletion of six nucleotides in exon 2 with the resultant loss of amino acids Leu¹¹⁴ and Glu¹¹⁵, representing the first alteration found in the cofactor-binding domain. The deletion mutant, expressed in HEK-293 cells, showed an approximately 20-fold lower maximum velocity but increased apparent affinity for cortisol and corticosterone. In contrast, two additionally constructed substitutions, Glu¹¹⁵ to Gln or Lys, showed increased maximal velocity and apparent affinity for 11ß-hydroxyglucocorticoids. Functional analysis of wild-type and mutant proteins indicated that a disturbed conformation of the cofactor-binding domain, but not the missing negative charge of Glu¹¹⁵, led to the observed decreased activity of the deletion mutant. Considered together, these findings provide evidence for a role of Glu¹¹⁵ in determining cofactor-binding specificity of 11ßHSD2 and emphasize the importance of structure-function analysis to elucidate the molecular mechanism of AME.

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