Abstract
The syndrome of apparent mineralocorticoid excess (ME) is an inherited form of human hypertension thought to result from a deficiency of 11β–hydroxysteroid dehydrogenase (11βHSD). This enzyme normally converts cortisol to inactive cortisone and is postulated to thus confer specificity for aldosterone upon the mineralocorticoid receptor. We have analysed the gene encoding the kidney isozyme of 11βHSD and found mutations on both alleles in nine of 11 AME patients (eight of nine kindreds). These mutations markedly affect enzymatic activity. They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ward, R. Familial aggregation and genetic epidemiology of blood pressure. In Hypertension: Pathophysiology, Diagnosis, and Management. (eds Laragh, J.H. & Brenner, B.M.) 67–88 (Raven Press, New York, 1995).
Jeunemaitre, X. et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 71, 169–180 (1992).
White, P.C. et al. A mutation in CYP11B1 (Arg-448→His) associated with steroid 11β-hydroxylase deficiency in Jews of Moroccan origin. J. clin. Invest. 87, 1664–1667 (1991).
Kagimoto, M., Winter, J.S., Kagimoto, K., Simpson, E.R. & Waterman, M.R. Structural characterization of normal and mutant human steroid 17 alpha-hydroxylase genes: molecular basis of one example of combined 17 alpha-hydroxylase/17,20 lyase deficiency. Molec. Endocrinol. 2, 564–570 (1988).
Lifton, R.P. et al. A chimeric 11β-hydroxylase/aldosterone synthase gene cause glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992).
Pascoe, L. et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc. natn. Acad. Sci. U.S.A. 89, 8327–8331 (1992).
Shimkets, R.A. et al. Liddle's syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell 79, 407–414 (1994).
Hansson, J.H. et al. Human hypertension caused by mutation in the gamma subunit of the epithelial sodium channel: genetic heterogeneity of Liddle's syndrome. Nature Genet. (in the press).
Werder, E., Zachmann, M., Völlmin, J.A., Veyrat, R. & Prader, A. Unusual steroid excretion in a child with low renin hypertension. Res. Steroids 6, 385–389 (1974).
Sann, L., Revol, A., Zachmann, M., Legrand, J.C. & Bethenod, M. Unusual low plasma renin hypertension in a child. J. clin. Endocr. Metab. 43, 265–271 (1976).
Winter, J.S.D. & McKenzie, J.K. (1977). A syndrome of low-renin hypertension in children. In Juvenile Hypertension (eds New, M.I. & Levin, L.S.) 123–133 (Raven Press, New York, 1977).
New, M.I., Levine, L.S., Biglieri, E.G., Pareira, J. & Ulick, S. Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J. clin. Endocr. Metab. 44, 924–933 (1977).
Ulick, S., Ramirez, L.C. & New, M.I. An abnormality in steroid reductive metabolism in a hypertensive syndrome. J. clin. Endocr. Metab. 44, 799–802 (1977).
Ulick, S. et al. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J.clin. Endocr. Metab. 49, 757–764 (1979).
Shackleton, C.H.L., Honour, J.W., Dillon, M.J., Chantler, C. & Jones, R.W.A. Hypertension in a four-year-old child: gas chromatographic and mass spectrometric evidence for deficient hepatic metabolism of steroids. J. clin. Endocr. Metab. 50, 786–792 (1980).
Oberfield, S.E. et al. Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess. J. clin. Endocr. Metab. 56, 332–339 (1983).
Krozowski, Z.K. & Funder, J.W. Renal mineralocorticoid receptors and hippocampal corticosterone binding species have identical intrinsic steroid specificity. Proc. natn. Acad. Sci. U.S.A. 80, 6056–6060 (1983).
Arriza, J.L. et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237, 268–275 (1987).
Funder, J.W., Pearce, P.T., Smith, R. & Smith, A.IX. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242, 583–585 (1988).
Edwards, C.R.W. et al. Localization of 11-beta-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet ii, 986–989 (1988).
Stewart, P.M. et al. Mineralocorticoid activity of liquorice: 11 -beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet ii, 821–824 (1987).
Monder, C. et al. The syndrome of apparent mineralocorticoid excess: its association with 11β-dehydrogenase and 5β-reductase deficiency and some consequences for corticosteroid metabolism. J. clin. Endocr. Metab. 63, 550–557 (1986).
Ulick, S., Tedde, R. & Wang, J.Z. Defective ring A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess. J. clin. Endocr. Metab. 74, 593–599 (1992).
Ulick, S., Chan, C.K., Rao, K.N., Edassery, J. & Mantero, F. A new form of the syndrome of apparent mineralocorticoid excess. J. Steroid Biochem. 32, 209–212 (1989).
Shackleton, C.H.L., Rodriguez, J., Arteaga, E., Lopez, J.M. & Winter, J.S.D. Congenital 11β-hydroxysteroid dehydrogenase deficiency associated with juvenile hypertension: corticosteroid profiles of four patients and their families. Clin. Endocrinol. 22, 701–712 (1985).
Dimartino-Nardi, J. et al. New findings in apparent mineralocorticoid excess. Clin. Endocrinol. 27, 49–62 (1987).
Stewart, P.M., Corrie, J.E.T., Shackleton, C.H.L. & Edwards, C.R.W. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J. clin. Invest. 82, 340–349 (1988).
Monder, C. & White, P.C. 11β-Hydroxysteroid dehydrogenase. Vitam. Horm. 47, 187–271 (1993).
Lakshmi, V. & Monder, C. Purification and characterization of the corticosteroid dehydrogenase component of the rat liver 11β-hydroxysteroid dehydrogenase complex. Endocrinology 123, 2390–2398 (1988).
Agarwal, A.K., Monder, C., Eckstein, B. & White, P.C. Cloning and expression of rat cDNA encoding corticosteroid 11β-dehydrogenase. J. biol. Chem. 264, 18939–18943 (1989).
Agarwal, A.K., Tusie-Luna, M.T., Monder, C. & White, P.C. Expression of 11β-hydroxysteroid dehydrogenase using recombinant vaccinia virus. Molec. Endocrinol. 4, 1827–1832 (1990).
Monder, C. & Lakshmi, V. Corticosteroid 11β-dehydrogenase of rat tissue. Endocrinology 126, 2435–2443 (1990).
Krozowski, Z.K., Stuchberry, S., White, P.C., Monder, C. & Funder, J.W. Characterization of 11β-hydroxysteroid dehydrogenase gene expression: Identification of multiple unique forms of messenger ribonucleic acid in the rat kidney. Endocrinology 127, 3009–3013 (1990).
Tannin, G.M., Agarwal, A.K., Monder, C., New, M.I. & White, P.C. The human gene for 11β-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J. biol. Chem. 266, 16653–16658 (1991).
Nikkilä, H. et al. Defects in the HSD11 gene encoding 11β-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J. cin. endocrinol. Metab. 77, 687–691 (1993).
Rusvai, E. & Naray-Fejes-Toth, A. A new isoform of 11β-hydroxysteroid dehydrogenase in aldosterone target cells. J. biol. Chem. 268, 10717–10720 (1993).
Brown, R.W., Chapman, K.E., Edwards, C.R.W. & Seckl, J.R. Human placental 11 beta-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD+- dependent isoform. Endocrinology 132, 2614–2621 (1993).
Agarwal, A.K., Mune, T., Monder, C. & White, P.C. NAD+-dependent isoform of 11β-hydroxysteroid dehydrogenase: cloning and characterization of cDNA from sheep kidney. J. biol. Chem. 269, 25959–25962 (1994).
Albiston, A.L., Obeyesekere, V.R., Smith, R.E. & Krozowski, Z.S. Cloning and tissue distribution of the human 11-HSD type 2 enzyme. Molec. Cell Endocrinol. 105, R11–R17 (1994).
Agarwal, A.K., Rogerson, F.M., Mune, T. & White, P.C. Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11β-hydroxysteroid dehydrogenase. Genomics (in the press).
Andersson, S., Davis, D.L., Dahlbäck, H., Jörnvall, H. & Russell, D.W. Cloning, structure, and expression of the mitochondria! cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J. biol. Chem. 264, 8222–8229 (1989).
Obeid, J. & White, P.C. Tyr-179 and Lys-183 are essential for enzymatic activity of 11β-hydroxysteroid dehydrogenase. Biochem. Biophys. Res. Commun. 188, 222–227 (1992).
Ghosh, D. et al. Three-dimensional structure of holo 3α,20β-hydroxysteroid dehydrogenase: a member of the short chain dehydrogenase family. Proc. natn. Acad. Sci. U.S.A. 88, 10064–10068 (1991).
Balvay, L., Libri, D. & Fiszman, M.Y. Pre-mRNA secondary structure and the regulation of splicing. BioEssays 15, 165–169 (1993).
Speiser, P.W. et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. clin. Invest. 90, 584–595 (1992).
Kornel, L., Starnes, W.R., Hill, S.R. Jr., & Hill, A. Studies on steroid conjugates: VI. Quantitative paper chromatography of urinary corticosteroids in essential hypertension. J. clin. Endocr. 29, 1608–1617 (1969).
Soro, A., Ingram, M.C., Tonolo, G., Glorioso, N. & Fraser, R. Evidence of coexisting changes in 11β-hydroxysteroid dehydrogenase and 5β-reductase activity in subjects with untreated essential hypertension. Hypertension 25, 67–70 (1995).
Walker, B.R., Stewart, P.M., Shackleton, C.H.L., Padfield, P.L. & Edwards, C.R.W. Deficient inactivation of cortisol by 11β-hydroxysteroid dehydrogenase in essential hypertension. Clin. Endocrinol. 39, 221–227 (1993).
Stewart, P.M., Rogerson, F.M. & Mason, J.I. Type 2 11β-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J. clin. Endocr. Metab. 80, 885–890 (1995).
Bennediktsson, R., Lindsay, R.S., Noble, J., Seckl, J.R. & Edwards, C.R.W. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341, 339–341 (1993).
Barker, D.J.P., Bull, A.R., Osmond, C. & Simmonds, S.J. Fetal and placental size and risk of hypertension in adult life. Lancet 301, 259–262 (1990).
Wyman, A.R. & White, R.A. A highly polymorphic locus in human DNA. Proc. natn. Acad. Sci. U.S.A. 77, 6754–6758 (1980).
Saiki, R.K. et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239, 487–491 (1988).
Filichkin, S.A. & Gelvin, S.B. Effect of dimethyl sulfoxide concentration on specificity of primer matching in PCR. Bio Techniques 12, 828–830 (1992).
Winship, P.R. An improved method for directly sequencing PCR amplified material using dimethyl sulfoxide. Nucl. Acids Res. 17, 1266 (1989).
Higuchi, R. Recombinant PCR. In PCR Protocols (eds Innis, M.A., Gelfand, D.H., Sninsky, J.J. & White, T.J.) 177–183 (Academic, San Diego,1990).
Agarwal, A.K., Mune, T., Monder, C. & White, P.C. Mutations in putative glycosylation sites of rat 11β-hydroxysteroid dehydrogenase affect enzymatic activity. Biochem. Biophy. Acta 1248, 70–74 (1995).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mune, T., Rogerson, F., Nikkilä, H. et al. Human hypertension caused by mutations in the kidney isozyme of 11β–hydroxysteroid dehydrogenase. Nat Genet 10, 394–399 (1995). https://doi.org/10.1038/ng0895-394
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0895-394
This article is cited by
-
Apparent mineralocorticoid excess: comprehensive overview of molecular genetics
Journal of Translational Medicine (2022)
-
Monogenic forms of low-renin hypertension: clinical and molecular insights
Pediatric Nephrology (2022)
-
Novel metabolomic profile of subjects with non-classic apparent mineralocorticoid excess
Scientific Reports (2021)
-
Molekulargenetik der humanen Hypertonie
Der Internist (2021)
-
The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway
Journal of Human Hypertension (2019)