This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Portrat-Doyen, S. Articles by Morel, Y. Search for Related Content PubMed PubMed Citation Articles by Portrat-Doyen, S. Articles by Morel, Y.

Isolated Aldosterone Synthase Deficiency Caused by Simultaneous E198D and V386A Mutations in the CYP11B2 Gene¹

Laboratoire de Biochimie Endocrinienne (S.P.-D., Y.M.), INSERM U329, Université de Lyon et Hôpital Debrousse, 69322 Lyon Cedex 05; Clinique Endocrinologique (J.T.), Hôpital de l’Antiquaille, 69321 Lyon Cedex 05; Département de Pédiatrie (O.R.), Hôpital-Nord, 42055, Saint-Etienne; INSERM U36 (P.M., K.M.C., L.P.), Collège de France, 75005 Paris; Laboratoire d’étude des minéralocorticoïdes (B.A.-F.), CHU Pitié-Salpétrière, 75634 Paris, France

Address all correspondence and requests for reprints to: Professor Yves Morel, INSERM U329, Laboratoire de Biochimie endocrinienne et moléculaire, Hôpital Debrousse, 29, rue Soeur Bouvier, 69322 Lyon Cedex 05, France; E-mail: morel{at}lyon151.inserm.fr

Isolated deficiencies in aldosterone biosynthesis are caused by mutations in the CYP11B2 (aldosterone synthase) gene. Patients with this deficiency have impaired aldosterone synthesis, exhibit increased plasma renin activity, secrete increased amounts of the steroid precursors DOC, corticosterone, and 18OHDOC, and are subject to salt wasting and poor growth. Two forms are generally distinguished. The first, corticosterone methyloxidase type I (CMO I or type 1 deficiency), is characterized by no detectable aldosterone secretion, a low or normal secretion of the steroid 18OHB, and are always found to have mutations that completely inactivate the encoded CYP11B2 enzyme. The second form (CMO II or type 2 deficiency) may have low to normal levels of aldosterone, but at the expense of greatly increased secretion of its immediate precursor 18OHB. These patients usually have a CYP11B2 enzyme with some residual enzymatic activity, especially 11ß-hydroxylase activity. We have studied two twins with an isolated aldosterone synthase activity who have a clinical profile typical of the type 1 deficiency. Their CYP11B2 genes are homozygous for three sequence changes, R173K, E198D, and V386A. In transfection assays these substitutions individually have modest effects on the encoded enzyme, but when found together they result in an enzyme with a decreased 11ß-hydroxylase activity, a large decrease of 18-hydroxylase activity, and no detectable 18-oxidase activity. This residual activity is more typical of that observed in patients classified as having CMO II deficiency, rather than CMO I deficiency, where no activity is detectable. This disparity between the CYP11B2 enzyme with residual activity and a clinical phenotypic typical of the type 1 deficiency, suggests that phenotype genotype relationships are not yet fully understood.

This article has been cited by other articles:

				M. Barr, S. M. MacKenzie, E. C. Friel, C. D. Holloway, D. M. Wilkinson, N. J.R. Brain, M. C. Ingram, R. Fraser, M. Brown, N. J. Samani, et al. Polymorphic Variation in the 11{beta}-Hydroxylase Gene Associates With Reduced 11-Hydroxylase Efficiency Hypertension, January 1, 2007; 49(1): 113 - 119. [Abstract] [Full Text] [PDF]

				S. Farese, K. Shojaati, B. Kadereit, F. J. Frey, and M. G. Mohaupt Blood pressure reduction in pregnancy by sodium chloride Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1984 - 1987. [Full Text] [PDF]

				T. H. Johannsen, D. Mallet, H. Dige-Petersen, J. Muller, K. M. Main, Y. Morel, and M. G. Forest Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3{beta}-Hydroxysteroid Dehydrogenase Deficiency J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2076 - 2080. [Abstract] [Full Text] [PDF]

				T. A. Williams, P. Mulatero, M. Bosio, S. Lewicka, M. Palermo, F. Veglio, and D. Armanini A Particular Phenotype in a Girl with Aldosterone Synthase Deficiency J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3168 - 3172. [Abstract] [Full Text] [PDF]

				F. M. Dunlop, P. A. Crock, J. Montalto, J. W. Funder, and K. M. Curnow A Compound Heterozygote Case of Type II Aldosterone Synthase Deficiency J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2518 - 2526. [Abstract] [Full Text] [PDF]

				G. Pinto, V. Tardy, C. Trivin, C. Thalassinos, S. Lortat-Jacob, C. Nihoul-Fekete, Y. Morel, and R. Brauner Follow-Up of 68 Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Relevance of Genotype for Management J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2624 - 2633. [Abstract] [Full Text] [PDF]

				K. M. Kayes-Wandover, G. M. Tannin, D. Shulman, D. Peled, K. L. Jones, L. Karaviti, and P. C. White Congenital Hyperreninemic Hypoaldosteronism Unlinked to the Aldosterone Synthase (CYP11B2) Gene J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5379 - 5382. [Abstract] [Full Text] [PDF]

				K. Ranade, K. D. Wu, N. Risch, M. Olivier, D. Pei, C.-F. Hsiao, L.-M. Chuang, L.-T. Ho, E. Jorgenson, R. Pesich, et al. Genetic variation in aldosterone synthase predicts plasma glucose levels PNAS, October 25, 2001; (2001) 221467098. [Abstract] [Full Text] [PDF]

				S. Portrat, P. Mulatero, K. M. Curnow, J.-L. Chaussain, Y. Morel, and L. Pascoe Deletion Hybrid Genes, due to Unequal Crossing Over between CYP11B1 (11{beta}-Hydroxylase) and CYP11B2(Aldosterone Synthase) Cause Steroid 11{beta}-Hydroxylase Deficiency and Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3197 - 3201. [Abstract] [Full Text] [PDF]

				K. M. Kayes-Wandover, R. E. L. Schindler, H. C. Taylor, and P. C. White Type 1 Aldosterone Synthase Deficiency Presenting in a Middle-Aged Man J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1008 - 1012. [Abstract] [Full Text]

				C. Deneux, V. Tardy, A. Dib, E. Mornet, L. Billaud, D. Charron, Y. Morel, and F. Kuttenn Phenotype-Genotype Correlation in 56 Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 207 - 213. [Abstract] [Full Text]

				D. l’Allemand, V. Tardy, A. Grüters, D. Schnabel, H. Krude, and Y. Morel How a Patient Homozygous for a 30-kb Deletion of the C4-CYP 21 Genomic Region Can Have a Nonclassic Form of 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4562 - 4567. [Abstract] [Full Text]

				O. Chabre, S. Portrat-Doyen, P. Chaffanjon, J. Vivier, P. Liakos, F. Labat-Moleur, E. Chambaz, Y. Morel, and G. Defaye Bilateral Laparoscopic Adrenalectomy for Congenital Adrenal Hyperplasia with Severe Hypertension, Resulting from Two Novel Mutations in Splice Donor Sites of CYP11B1 J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4060 - 4068. [Abstract] [Full Text]

				P. Mulatero, D. Schiavone, F. Fallo, F. Rabbia, C. Pilon, L. Chiandussi, L. Pascoe, and F. Veglio CYP11B2 Gene Polymorphisms in Idiopathic Hyperaldosteronism Hypertension, March 1, 2000; 35(3): 694 - 698. [Abstract] [Full Text] [PDF]

				New Insight into the Molecular Basis of 3{beta}-Hydroxysteroid Dehydrogenase Deficiency: Identification of Eight Mutations in the HSD3B2 Gene in Eleven Patients from Seven New Families and Comparison of the Functional Properties of Twenty-Five Mutant Enzymes J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4410 - 4425. [Abstract] [Full Text]

				K. Ranade, K. D. Wu, N. Risch, M. Olivier, D. Pei, C.-F. Hsiao, L.-M. Chuang, L.-T. Ho, E. Jorgenson, R. Pesich, et al. Genetic variation in aldosterone synthase predicts plasma glucose levels PNAS, November 6, 2001; 98(23): 13219 - 13224. [Abstract] [Full Text] [PDF]