Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism

Kawamoto, Takeshi; Mitsuuchi, Yasuhiro; Ohnishi, Tsukasa; Ichikawa, Yoshiyuki; Yokoyama, Yuichi; Sumimoto, Hidetoshi; Toda, Katsumi; Miyahara, Katsunori; Kuribayashi, Isao; Nakao, Kazuwa; Hosoda, Kiminori; Yamamoto, Yasutake; Imura, Hiroo; Shizuta, Yutaka

doi:10.1016/s0006-291x(05)81058-7

Cited by 153 publications

(80 citation statements)

References 25 publications

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“…Three mRNAs, 4.2, 3.6, and 2.2 kb in length, were detected with an oligonucleotide probe corresponding to sequence at the 3' end of CYPIIBI (which will not detect the hybrid mRNA). The different mRNA lengths are assumed to result from alternate usage of different polyadenylation signals and are similar to the sizes observed in a previous analysis of mRNA from cultured adrenal cells (24) and an aldosterone-secreting tumor (1). The Figure 3.…”

Section: Methodssupporting

confidence: 52%

“…In the normal human adrenal cortex the terminal steps in cortisol and aldosterone biosynthesis are mediated by the cytochrome P450 enzymes CYP1 B 1 (1 1/,-hydroxylase) and CYP1 1B2 (aldosterone synthase), respectively ( 1,2), which are encoded by two highly similar genes located on chromosome 8q22 (3). In the zona fasciculata the 17-hydroxylated steroid precursor, 11-deoxycortisol, is hydroxylated at the 1 1,6 position by CYPllB 1 to produce cortisol.…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

Pascoe¹,

Jeunemaı̂tre²,

Lebrethon³

et al. 1995

J. Clin. Invest.

132

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Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP1IB1/CYPJ1B2 gene which has arisen from an unequal crossing over between the two CYPJJB 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 CYPIIB gene was demonstrated to be expressed at higher levels than either CYPlJBI or CYPIJB2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYPIJBI 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. (J. Clin. Invest. 1995. 96:2236-2246

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Section: Methodssupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

Pascoe¹,

Jeunemaı̂tre²,

Lebrethon³

et al. 1995

J. Clin. Invest.

132

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“…In humans, two genes encoding 11/3-hydroxylase, CYP11B1(P45011~ gene) and CYP11B2 (P450aldo gene; aldosterone synthase cytochrome P450 gene) were identified [27][28][29]. P450aldo shows all three catalytic activities (11/3-hydroxylase, 18-hydroxylase, and 18-oxidase) on DOC, a substrate of aldosterone, when P450aldo cDNA was expressed in COS-7 cells [28].…”

Section: Discussionmentioning

confidence: 99%

“…P450aldo shows all three catalytic activities (11/3-hydroxylase, 18-hydroxylase, and 18-oxidase) on DOC, a substrate of aldosterone, when P450aldo cDNA was expressed in COS-7 cells [28]. Since the antibody to P45011k we used here crossreacts with P450aldo, it is possible that this antibody may detect P450aldo, but specific mRNA, enzyme activities, and the immunoreactivity of P450aldo are generally below the level of detection in the normal adrenal [27,29].…”

Section: Discussionmentioning

confidence: 99%

A Case of Deoxycorticosterone-Producing Adrenal Adenoma.

et al. 1995

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Abstract. A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin activity and the aldosterone concentration were low, while the DOC concentration was high (6.10-10.3 ng/ml; normal range 0.03-0.33). Plasma cortisol, androgens, and estrogens as well as urinary 17-OHCS and 17-KS were within normal limits. Furosemide administration and two hours upright posture resulted in a 3-fold increase in plasma DOG, but the administration of ACTH, dexamethasone, or angiotensin III had no effect on plasma DOG. Following resection of a right adrenal tumor weighing 70 g, the hypertension and hypokalemia disappeared. DOG content in the tumor was high. On light microscopic examination, the tumor was encapsulated, composed of cells with clear cytoplasm and large nuclei and there were extensive areas of fibrosis and infiltration of lymphocytes. According to Weiss's criteria, the tumor was considered to be an adrenocortical adenoma. Immunohistochemically, P450scc, 3/3HSD, P450c21 and P45011~ were positive with heterogeneity of intra-tumoral expression. No immunoreactivity for P45017a in this adenoma was detected. This is different from a previous report in which a relatively small number of cells in DOG-secreting adrenocortical carcinoma were positive for P45017a•

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“…The pathway of the terminal aldosterone biosynthesis involves three sequential reactions: hydroxylation of 11-deoxycorticosterone at position 11b to form corticosterone, hydroxylation of corticosterone at position 18 to form 18-OH-corticosterone, and oxidation at position 18 to convert 18-OH-corticosterone to aldosterone. The terminal steps of aldosterone biosynthesis in the zona glomerulosa are catalysed by a single cytochrome P450 enzyme termed aldosterone synthase (P450c11Aldo) (1). The gene encoding for P450c11Aldo has been cloned and is termed CYP11B2 (2).…”

Section: Introductionmentioning

confidence: 99%

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Peter

Bünger

Drop

et al. 1998

European Journal of Endocrinology

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We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2), presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism

Cited by 153 publications

References 25 publications

Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

A Case of Deoxycorticosterone-Producing Adrenal Adenoma.

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

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