[en] Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP11B1/CYP11B2 gene which has arisen from an unequal crossing over between the two CYP11B genes in a previous meiosis. We have studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed, giving a rare opportunity to study the regulation and action of the hybrid gene causing the disease. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. In cell culture experiments hybrid gene expression was stimulated by ACTH leading to increased production of aldosterone and the hybrid steroids characteristic of glucocorticoid-suppressible hyperaldosteronism. The genetic basis of the adrenal pathologies in this family is not known but may be related to the duplication causing the hyperaldosteronism.
Kawamoto, T., Y. Mitsuuchi, T. Ohnishi, Y. Ichikawa, Y. Yokoyama, H. Sumimoto, K. Toda, K. Miyahara, I. Kuribayashi, K. Nakao, et al. 1990. Cloning and expression of a cDNA for human cytochrome P450aldo as related to primary aldosteronism. Biochem. Biophys. Res. Commun. 169:245-252.
Curnow, K. M., M. T. Tusie-Luna, L. Pascoe, R. Natarajan, J. L. Gu, J. L. Nadler, and P. C. White. 1991. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol. Endocrinol. 5:1513-1522.
Mornet, E., J. Dupont, A. Vitek, and P. C. White. 1989. Characterization of two genes encoding human steroid 11β-hydroxylase (P45011β). J. Biol. Chem. 264:20961-20967.
Simpson, E. R., and M. R. Waterman. 1988. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Ann. Rev. Physiol. 50:427-440.
Quinn, S. J., and G. H. Williams. 1992. Regulation of aldosterone secretion. In The Adrenal Gland. V. H. T. James, editor. Raven Press, New York. 159-189.
Sutherland, D. J. A., J. L. Ruse, and J. C. Laidlaw. 1966. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can. Med. Assoc. J. 95:1109-1119.
New, M. I., and R. E. Peterson. 1967. A new form of congenital adrenal hyperplasia J. Clin. Endocrinol. & Metab. 27:300-305.
Ulick, S., M. D. Chu, and M. Land. 1983. Biosynthesis of 18-oxocortisol by aldosterone producing adrenal tissue. J. Biol. Chem. 258:5498-5502.
Gomez-Sanchez, C. E., M. Montgomery, A. Ganguly, O. B. Holland, E. P. Gomez-Sanchez, C. E. Grim, and M. H. Weinberger. 1984. Elevated urinary excretion of 18-oxocortisol in glucocorticoid-suppressible aldosteronism. J. Clin. Endocrinol. & Metab. 59:1022-1024.
Ulick, S., C. K. Chan, J. R. Gill, M. Gutkin, L. Letcher, F. Mantero, and M. I. New. 1990. Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism. J. Clin. Endocrinol. & Metab. 71:1151-1157.
Lifton, R. P., R. G. Dluhy, M. Powers, G. M. Rich, S. Cook, S. Ulick, and J. M. Lalouel. 1992. A chimaeric 11β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature (Lond.). 355:262-265.
Pascoe, L., K. M. Curnow, L. Slutsker, J. M. C. Connell, P. W. Speiser, M. I. New, and P. C. White. 1992. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc. Natl. Acad. Sci. USA. 89:8327-8331.
Miyahara, K., T. Kawamoto, Y. Mitsuuchi, K. Toda, H. Imura, R. D. Gordon, and Y. Shizuta. 1992. The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity. Biochem. Biophys. Res. Commun. 189:885-891.
Lifton, R. P., R. G. Dluhy, M. Powers, G. M. Rich, M. Gutkin, F. Fallo, J. R. Gill, L. Feld, A. Ganguly, J. C. Laidlaw, et al. 1992. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat. Genet. 2:66-74.
Pascoe, L., K. M. Curnow, L. Slutsker, A. Rosler, and P. C. White. 1992. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc. Natl. Acad. Sci. USA. 89:4996-5000.
Sibony, M., J. M. Gasc, F. Soubrier, F. Alhenc-Gelas, and P. Corvol. 1993. Gene expression and tissue localization of the two isoforms of angiotensin I converting enzyme. Hypertension (Dallas). 21:827-835.
Sambrook, J., F. Fritsch, and T. Maniatis. 1989. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. 4 vols.
Lebrethon, M. C., D. Naville, M. Begeot, and J. M. Saez. 1994. Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II. J. Clin. Invest. 93:1828-1833.
Lebrethon, M. C.,. C. Jaillard, G. Defayes, M. Begeot, and J. M. Saez. 1994. Human cultured adrenal fasciculata-reticularis cells are targets for angiotensin II: effects on cytochrome P450 cholesterol side chain cleavage, cytochrome P450 17α-hydroxylase, and 3β-hydroxysteroid-dehydrogenase messenger ribonucleic acid and proteins and on steroidogenic responsiveness to corticotropin and angiotensin II. J. Clin. Endocrinol. & Metab. 78:1212-1219.
Chomczynski, P., and N. Sacchi. 1987. Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162:156-159.
Gomez-Sanchez, C. E., L. M. Leon, and E. P. Gomez-Sanchez. 1992. Biotin-hydrazide derivatives for the development of steroid enzyme-linked immunoassays. J. Steroid Biochem. Mol. Biol. 43:523-528.
Gomez-Sanchez, C. E., M. F. Foecking, M. W. Ferris, M. R. Chavarri, L. Uribe, and E. P. Gomez-Sanchez. 1987. The production of monoclonal antibodies against aldosterone. Steroids. 49:581-587.
Jeunemaitre, X., A. Charru, L. Pascoe, T. T. Guyenne, B. Aupetit-Faisant, C. H. L. Shackleton, M. Schambelan, P. F. Plouin, and P. Corvol. 1995. Hyperaldostéronisme sensible à la dexaméthasone avec adénome surrénalien: etude clinique, biologique et génétique. La Presse Médicale. In press.
Ilvesmaki, V., and R. Voutilainen. 1991. Interaction of phorbol ester and adrenocorticotropin in the regulation of steroidogenic P450 genes in human fetal and adult adrenal cell cultures. Endocrinology. 128:1450-1458.
Matsuo, K., K. Kawai, H. Tsuchiyama, and Y. Ueki. 1985. Glucocorticoidsuppressible hyperaldosteronism: ultrastructural observation of a case. Acta Pathol. Jpn. 35:1511-1519.
Kato, S., M. Haji, T. Yanase, H. Nawata, K. Kato, and H. Ibayashi. 1988. A case of glucocorticoid-suppressible hyperaldosteronism with aldosterone producing adenoma. Endocrinol. Jpn. 35:311-320.
Miura, K., K. Yoshinaga, K. Goto, I. Katsushima, M. Maebashi, H. Demura, M. Iino, R. Demura, and T. Toraki. 1968. A case of glucocorticoid-responsive hyperaldosteronism. J. Clin. Endocrinol. & Metab. 28:1807-1815.
Ogishima, T., H. Suzuki, J. I. Hata, F. Mitani, and Y. Ishimura. 1992. Zone specific expression of aldosterone synthase cytochrome P450 and cytochrome P450-11β in rat adrenal cortex: histochemical basis for the functional zonation. Endocrinology. 130:2971-2977.
Domalik, I. J., D. D. Chaplin, M. S. Kirkman, R. C. Wu, W. Liu, T. A. Howard, M. F. Seldin, and K. L. Parker. 1991. Different isozymes of mouse 11β hydroxylase produce mineralocorticoids and glucocorticoids. Mol. Endocrinol. 5:1853-1861.
Ohnishi, T., A. Wada, M. Lauber, T. Yamano, and M. Okamoto. 1988. Aldosterone biosynthesis in mitochondria of isolated zones of the adrenal cortex. J. Steroid Biochem. 31:73-81.
Sasano, H., M. Okamoto, and N. Sasano. 1988. Immunohistochemical study of cytochrome P450 11β-hydroxylase in human adrenal cortex with mineralo- and glucocorticoid excess. Virchows Archiv. A Pathol. Anat. 413:313-318.
Nonaka, Y., M. Okamoto, K. Morahashi, S. Kirita, T. Hashimoto, and T. Omura. 1992. Functional expression of cDNAs for bovine 11β-hydroxylase-aldosterone synthases, P450(11β)-2 and -3 and their chimeras. J. Steroid Biochem. 41:779-780.
Yanigabashi, K., M. Haniu, J. E. Shively, W. H. Shen, and P. Hall. 1986. The synthesis of aldosterone by the adrenal cortex. Two zones (fasciculata and glomerulosa) possess one enzyme for 11β, 18-,hydroxylation and aldehyde synthesis. J. Biol. Chem. 261:3556-3562.
Ogishima, T., F. Mitani, and Y. Ishimura. 1989. Isolation of two distinct cytochromes P45011β with aldosterone synthase activity from Bovine adrenocortical mitochondria. J. Biochem. 105:497-499.
Curnow, K. M., L. Slutsker, J. Vitek, T Cole, P. W. Speiser, M. I. New, P. C. White, and L. Pascoe. 1993. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. Proc. Natl. Acad. Sci. USA. 90:4552-4556.
Kawamoto, T., Y. Mitsuuchi, K. Toda, Y. Yokoyama, K. Miyahara, S. Miura, T. Ohnishi, Y. Ichikawa, K. Nakao, H. Imura, S. Ulick, and Y. Shizuta. 1992. Role of steroid 11β-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc. Natl. Acad. Sci. USA. 89:1458-1462.
Pascoe, L., and K. M. Curnow. 1995. Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure. Steroids. 60:22-27.
Oberfield S. E., L. S. Levine, E. Stoner, D. Chow, W. Rauh, F. Greig, S. M. Lee, E. Lightner, M. Witte, and M. I. New. 1981. Adrenal glomerulosa function in patients with dexamethasone-suppressible hyperaldosteronism. J. Clin. Endocrinol. & Metab. 53:158-164.
Jefcoate, C. R., B. C. McNamara, I. Artemenko, and T. Yamazaki. 1992. Regulation of cholesterol movement to mitochondrial cytochrome P450scc in steroid hormone synthesis. J. Steroid Biochem. 43:751-767.