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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1633-1637
Copyright © 1999 by The Endocrine Society

Original Studies

Genetic Analysis of Aldosterone Synthase in Patients with Idiopathic Hyperaldosteronism1

Yoshiyu Takeda, Kenji Furukawa, Satoru Inaba, Isamu Miyamori and Hiroshi Mabuchi

Second Department of Internal Medicine (Y.T., K.F., H.M.), Department of Health Sciences (Y.T.), School of Medicine, Kanazawa University, Kanazawa 920, Japan; and Third Department of Internal Medicine (S.I., I.M.), Fukui Medical School, Fukui 910–11, Japan

Address all correspondence and requests for reprints to: Yoshiyu Takeda, M.D., Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13–1 Takara-machi, Kanazawa 920, Japan. E-mail: takeday{at}mhs.mp.kanazawa-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Idiopathic hyperaldosteronism (IHA) is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. We compared activity of aldosterone synthase and expression of CYP11B2 messenger RNA (mRNA) in mononuclear leukocytes (MNL) from patients with IHA to findings in leukocytes from patients with aldosterone-producing adenoma and normal controls. Aldosterone synthase activity was estimated from conversion of [14C]deoxycorticosterone to [14C]aldosterone. Levels of CYP11B2 mRNA were determined by competitive PCR. In the same subjects, we sought the chimeric CYP11B1/CYP11B2 that is candidate gene for glucocorticoid-remediable hyperaldosteronism. Southern blot analysis and a long PCR method were used to detect the chimeric gene. Direct sequencing of the CYP11B2 also was performed. No chimeric genes or mutations in the coding region of the CYP11B2 were found in genomic DNA from these patients. However, both aldosterone synthase activity and CYP11B2 mRNA expression were greater in mononuclear leukocytes of patients with IHA than those of patients with aldosterone-producing adenoma or controls. These results suggest that regulatory factors of the CYP11B2 gene, e.g. unidentified aldosterone-stimulating substances or abnormalities in the promoter region of the CYP11B2 gene in patients with IHA resulting in oversecretion, may cause overexpression of mRNA of CYP11B2.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE SYNDROME of primary aldosteronism is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. The most common clinical subtypes of primary aldosteronism are aldosterone-producing adrenocortical adenoma (APA) and bilateral adrenal cortical hyperplasia (idiopathic hyperaldosteronism, or IHA). Glucocorticoid-remediable hyperaldosteronism (GRA), a rare variety of primary aldosteronism showing autosomal dominant inheritance, is characterized by unusual sensitivity of aldosterone secretion to ACTH, which becomes predominant over the renin-angiotensin system, in regulation of aldosterone secretion (1). IHA represents about 10–30% of all cases of primary aldosteronism (2), usually characterized by milder biochemical and hormonal abnormalities than those occurring with adenomas.

In the adrenal cortex, aldosterone is synthesized from deoxycorticosterone (DOC) by a mitochondrial cytochrome P450 enzyme, aldosterone synthase (CYP11B2) (3). The corresponding gene is located on chromosome 8q22, adjacent to a closely related gene that encodes steroid 11ß-hydroxylase (CYP11B1), which is required for cortisol biosynthesis. Mutations in CYP11B2 can cause aldosterone deficiency (4). Conversely, GRA is caused by genetic recombination between CYP11B1 and CYP11B2 that increases expression of CYP11B2 messenger RNA (mRNA) and leads to inappropriate secretion of aldosterone (5, 6, 7). Recently, mutations in the CYP11B2 gene that increase the activity of this enzyme up to 1000-fold have been reported in genetically hypertensive rats (8). Fardella et al. (9) showed that the mutations in human CYP11B2 gene, as seen in rats, increased the enzyme activity to 4-fold. To clarify the etiology of IHA, we estimated aldosterone synthase activity and expression of CYP11B2 mRNA in peripheral mononuclear leukocytes (MNL) of patients with IHA, in comparison with patients with APA and normal controls. Then, searching for mutations in the CYP11B2 gene, as mentioned above, we looked for the chimeric CYP11B1/CYP11B2 gene in patients with IHA and APA and analyzed the coding region of the CYP11B2 gene using direct sequencing methods.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Nineteen patients with primary aldosteronism, including 10 with APA (4 male and 6 female; ages, 35–62 yr) and 9 with IHA (3 males and 6 females; ages, 32–60 yr) were studied, as well as control subjects (6 males and 4 females; ages, 30–50 yr). All patients were diagnosed from characteristic biochemical abnormalities, including hypokalemia, suppressed PRA, and increased aldosterone production. GRA was excluded by administering 2 mg/day dexamethasone to patients for 3 days. If dexamethasone failed to suppress plasma aldosterone to the normal range and serum potassium and blood pressure did not normalize, a clinical diagnosis of primary aldosteronism was made. High concentrations of plasma aldosterone in both adrenal veins, and absence of a solitary adenoma on CT scan of the adrenal glands, confirmed a diagnosis of IHA. Other biochemical parameters, including low serum potassium concentrations (APA, 2.6 ± 0.3 mmol/L; IHA, 2.8 ± 0.4 mmol/L), suppressed PRA (APA, 0.61 ± 0.17 ng/L·sec; IHA, 0.79 ± 0.21 ng/L·sec), and high plasma aldosterone concentrations (APA, 1530 ± 290 pmol/L; IHA, 1140 ± 330 pmol/L) were similar in both groups with hyperaldosteronism.

Measurement of aldosterone synthase activity

Peripheral MNL were prepared by standard techniques (10). Aldosterone synthase activity in 106 mol/MNL was assayed by replacing the medium containing 0.5 µmol/L [14C]DOC (0.001 µCi; New England Nuclear, Tokyo, Japan) and incubating the cells for 24 h. The incubation medium was extracted with a Sep-Pak C18 cartridge (Waters Associates, Milford, CT), and chromatography was performed in a reverse-phase high-performance liquid chromatography system, as previously reported (11). The activity of aldosterone synthase was estimated as the percent conversion of the total radioactivity of [14C]DOC to [14C]aldosterone.

Competitive PCR assay of CYP11B2 mRNA

Total cellular RNA, isolated from peripheral MNL of patients with IHA, those with APA, and normal controls, was amplified by an RT-PCR, as previously described (11). Briefly, 500 ng of total RNA was incubated at 42 C for 60 min with 2.5 U of Moloney murine leukemia virus reverse transcriptase (Takara, Tokyo, Japan) in a 20-µL reaction volume containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 5 mmol/L MgCl2, each deoxynucleotide triphosphate at 1 mmol/L, and 2.5 mmol/L random hexanucleotide primer (Takara). This mixture was incubated for 5 min at 99 C. The single-stranded complementary DNA (cDNA) was used for competitive PCR. The sequences of sense and antisense primers for CYP11B2 were 5'-TACAGGTTTTCCTCTACTCG-3' and 5'-AGATGCAAGAC-TAGTTAATC-3', following the sequences published by Wu et al. (12) and respectively corresponding to nucleotides 1208–1227 and 1503–1522 of their own cDNA (13). The competitive templates for CYP11B2 were made using the PCR MIMIC Construction Kit (CLONTECH Laboratories, Inc., Palo Alto, CA). After quantification, a serial dilution was used as an internal standard for competitive PCR, which was performed using 2.5 µL of the reverse-transcribed DNA, 2 µL of various concentrations of the competitive template, 0.5 µmol/L each of sense and antisense primers, and 0.5 U of Taq DNA polymerase (Perkin-Elmer Japan, Tokyo, Japan) in 50 µL of 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, and 2 mmol/L MgCl2 with each deoxynucleotide triphosphate at 0.2 mmol/L. The reactions were performed for 1 min at 94 C, 1 min at 59 C, and 2 min at 72 C for 30 cycles. Aliquots of 10 µL of amplification products were electrophoresed on a 3.0% agarose gel, which then was stained with ethidium bromide and photographed. Staining intensity was quantified by computer-assisted densitometry using the BIO-PROFIL BIO-1D system (Compak, Tokyo, Japan). Intensities of each product from cDNA and those from competitive templates were plotted as a function of the known amounts of the competitive templates. Intraassay and interassay variabilities of this competitive PCR were 11.5% and 14.8%, respectively. The concentration of CYP11B2 mRNA was expressed as attomoles per 100 nanograms of total RNA. To test the yield and efficiency of the reverse transcriptase reaction, 1 µg of total RNA was subjected to RT as above, with 5 µmol/L of radioactively labeled [32P]deoxycycidine triphosphate (New England Nuclear) added to the reaction, as previously reported (14).

Southern blotting of RT-PCR products

The RT-PCR products were electrophoresed in 10-µL aliquots on a 3% agarose gel and transferred to nylon membranes. Hybridization was performed as previously reported (15), using an oligoprobe specific for CYP11B2 (5'-GGCGCGTGGCAGAGGCAGAGATGCTGC-3') that had been end-labeled with [32P]ATP (6000 Ci/mmol, New England Nuclear) using a 5'-end oligonucleotide labeling kit.

Southern analysis of genomic DNA

Genomic DNA was extracted from peripheral blood leukocytes and digested with BamHI, fractionated by agarose gel electrophoresis, transferred to a nylon membrane, and hybridized with a 32P-deoxycycidine triphosphate-labeled exon 3–4 probe corresponding to 11ß-hydroxylase (5). The probe was prepared by PCR using specific primers and genomic DNA as a template. DNA samples from a patient with GRA (kindly donated by Dr. Gordon, University Department of Medicine, Greenlopes Hospital, Brisbane, Australia) and from healthy volunteers were used as controls.

Analysis of DNA using a long PCR

Genomic DNA was extracted from peripheral blood leukocytes. For each patient, the isolated DNA was subjected to two amplification reactions, as previously reported by Jonsson et al. (16). In brief, in the first reaction, the sense primer (5'-TCCTTCATCTACCTTTGGCTGGGG-3') was specific for the 5' untranslated region of the aldosterone synthase gene, whereas in the second reaction, the sense primer (5'-TCATGCACCCCCAATGAGTCCCTG-3') was specific for the untranslated region of the 11ß-hydroxylase gene. For both reactions, the antisense primer (5'-GAGTCCTCCAGCTGCCTCTCAACC-3') was specific for the intron E region of the aldosterone synthase gene. The DNA was amplified by the methods previously described. Amplification products were electrophoresed on 0.8% agarose gels, stained with ethidium bromide, and visualized under ultraviolet light.

Sequence analysis of CYP11B2

Sequence analysis of the CYP11B2 gene in patients with IHA or APA was performed by PCR amplification of exons using both intron- and exon-derived primers, as previously reported (17). PCR products were cycle-sequenced with Taq polymerase FS dye-terminator sequencing kits (Perkin-Elmer Japan) on a model 377 automated DNA sequencer (Perkin-Elmer Japan).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The activity of aldosterone synthase in MNL was significantly increased in patients with IHA (15 ± 3.2%), compared with patients with APA (4.9 ± 2.8%) and normal controls (5.8 ± 3.1%, n = 10; P < .05). Previously, we measured the activity of aldosterone synthase in aldosteronoma and found that the activity was 25–33% when incubation time was 2 h (unpublished data). According to these results, aldosterone synthase activity in MNL was much less than that in aldosteronoma. The upper panel of Fig. 1Go shows the data from Southern blotting of RT-PCR products of CYP11B2 mRNA. The expression of CYP11B2 mRNA in MNL is about 1/100 of that in adrenal gland. Greater expression of CYP11B2 mRNA was observed in aldosteronoma, and lower expression was seen in the adjacent adrenal tissue, in comparison to adrenal glands.



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  		Figure 1. The expression of CYP11B2 mRNA, using Southern blotting of RT-PCR in MNL, APA, adjacent adrenal tissue (Aj), and normal adrenal tissue (Ad), which was obtained from a patient with renal cell carcinoma (upper panel). The lower panel shows the analysis of relative changes in CYP11B2 mRNA concentrations, by competitive PCR. Increasing the concentration of competitive template for CYP11B2, from 0 to 80 x 10-3 attomoles/µL, increasingly inhibited the amplification of endogenous CYP11B2 cDNA in the MNL.

 
The lower panel of Fig. 1Go illustrates that increasing concentrations of each competitive template for CYP11B2, from 0–80 x 10-3 attomoles/µL, increasingly inhibited the amplification of endogenous CYP11B2 cDNA. When PCR was carried out in the absence of RT, no band was seen at 471 bp. CYP11B2 mRNA levels in patients with IHA were significantly elevated, compared with those in patients with APA and those in normal controls (P < .05, Fig. 2Go).



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  		Figure 2. The concentration of CYP11B2 mRNA in MNL of patients with IHA, those with APA, and normal subjects. CYP11B2 mRNA levels were significantly increased in IHA, compared with APA or normal subjects (P < 0.05).

 
DNA extracted from APA or IHA patients never yields the 6.2-BamHI fragments characteristic of the GRA chimeric gene (Fig. 3Go). By the long PCR method of GRA chimeric gene detection, the 3.9-kb fragment resulting when the GRA chimeric gene was amplified was not seen in patients with IHA or APA. No mutations were found in the exons of CYP11B2 in any of the patients. The intron-exon junctions also seemed intact.



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  		Figure 3. Southern blot analysis of genomic DNAs of patients with IHA, those with GRA, and a normal control subject. The DNAs were digested with BamHI (upper panel). The fragment of 6.2 kb was not detected in IHA and control. Lower panel shows the analysis of DNA using long PCR followed by electrophoresis, ethidium bromide staining, and visualization under ultraviolet light, in a normal subject (C), patients with GRA, IHA (lanes 1–4), and APA (lanes 5 -8). The remainder of IHA or APA showed the same result. A, aldosterone synthase gene; H, hybrid gene.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we demonstrated increases in activity of aldosterone synthase and expression of CYP11B2 mRNA levels in MNL of patients with IHA, in comparison with patients with APA or normal controls. In a tissue specimen from an aldosteronoma, expression of CYP11B2 mRNA was greater than in adjacent adrenal tissue. 21-Hydroxylase and 11ß-hydroxylase have been reported in a benign testicular Leydig cell tumor (18, 19). Previously, we have reported both synthesis of aldosterone and expression of CYP11B2 in blood vessels (11, 15, 20), and Gomez-Sanchez et al. (21) recently have reported the synthesis of aldosterone in brain tissue. Several reports have described various enzyme activities in macrophages and monocytes, including renin (22) and 5{alpha}-reductase (23). Shozu et al. (24) have reported estrogen biosynthesis in THP1 cells of human mononuclear leukemic origin, as well as aromatase activity and expression of CYP19 mRNA in human MNL (personal communication). These results suggest that MNL may possess steroid biosynthetic enzyme activities. Glucocorticoid synthesis and the expression of CYP11B1 mRNA in blood vessels were also reported (11, 15). However, we could only detect small a amount of CYP11B1 mRNA in MNL by performing repeated PCR. In vascular endothelial cells, the amount of CYP11B1 mRNA is reported to be very small, compared with that of CYP11B2 (11). The reason for this is unclear.

Increased expression of CYP11B2 mRNA in MNL of patients with IHA may only reflect increased aldosterone synthesis in adrenal tissues; we have reported increased production of aldosterone in adrenal tissue involved by IHA (25). In this study, the expression of CYP11B2 mRNA in MNL was very small, compared with that in aldosteronoma or adrenal gland. The activity of aldosterone synthase in MNL was much less than that in aldosteronoma or adrenal gland. These results may suggest that the actual potential of MNL to contribute to production of aldosterone in vivo is little.

The presence of bilateral hyperplasia in IHA suggests a secondary response to a stimulatory mechanism, rather than a primary neoplastic growth, although no novel aldosterone-stimulating substance has been identified. Recently, Shozu et al. (26) have reported that a mutation in a 5'-flanking region of the CYP19 gene caused excessive peripheral aromatase expression in a boy with gynecomastia. Several reports suggest that polymorphisms in the CYP11B2 5'-flanking region may be involved with cardiovascular diseases (27, 28), associated with adrenocortical function in males (29), or useful in genetic diagnosis of 11ß-hydroxylase gene defects (30). Further analysis of the promoter region of CYP11B2 in patients with IHA is necessary.

The etiology of primary aldosteronism has been unknown since Conn first described it in 1955. However, Lifton et al. (5) have reported the candidate gene underlying the clinical entity of GRA, which was described by Sutherland et al. (31) in 1966. Focal or diffuse hyperplasia usually is present in both the remainder of the adrenal containing the APA and the contralateral gland. Gordon et al. (1) have postulated that such histologic hyperplasia outside the adenoma suggests a genetic abnormality not limited to the adenoma cells. Pascoe et al. (7) have reported that GRA chimeric gene-transfected cells possess aldosterone synthase activity. They also demonstrated that the GRA chimeric gene was expressed at higher levels than either CYP11B1 or CYP11B2 in the adrenal cortex of GRA patients (32). Gordon et al. (33) have identified 11 families with 2 or more members who had adenomas that did not show suppression by glucocorticoids, suggesting that the genetic abnormalities may be involved more frequently in primary aldosteronism than is now appreciated. However, Carroll et al. (34) were unable to detect a GRA chimeric gene in any APAs, and the GRA gene may not be involved in APAs. Recently Jonsson et al. (16) have described the long PCR procedure, which is a relatively fast, safe, and inexpensive method for diagnosis of GRA. In the present study, we could not detect the GRA chimeric gene in patients with APA or IHA, using Southern analysis or the long PCR method. Mulatero et al. (35) also were unable to find the GRA gene in a large number of patients with primary aldosteronism. Recently, Beuschlein et al. (36) have reported the somatic, heterozygous microdeletion in CYP21B gene of APA. However, they concluded little pathophysiological significance of their findings. Nodular adrenal cortical hyperplasia is common in multiple endocrine neoplasia type I. Recently, a candidate gene for multiple endocrine neoplasia type I, menin gene, has been cloned (37). We analyzed the coding region of the menin gene in genomic DNA of IHA and tumor DNA of APA and did not find any abnormalities in both patients (data not shown).

Mutations in the coding region of CYP11B2 decrease or eliminate aldosterone synthase activity in familial hypoaldosteronism (4, 17). However, some artificial mutations of CYP11B2 have been shown to increase enzymatic activity (9). Fardella et al. (38) have reported that the Arg173 variant may be linked to low-renin hypertension in Chilean patients. However, we could not find any mutations in the coding region of CYP11B2 gene, including the Arg173 variant in patients with IHA or APA.

In conclusion, no GRA-associated chimeric gene and no mutations in the coding region of the CYP11B2 gene were found in patients with IHA or APA. However, overexpression of CYP11B2 mRNA in the MNL of patients with IHA suggests that unidentified aldosterone-stimulatory factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA.


   Footnotes
 
1 This work was supported, in part, by grants-in-aid for scientific research from the Ministry of Education, Science and Culture, Japan, and Hokkoku Cancer Research Foundation. Back

Received October 9, 1998.

Revised January 4, 1999.

Accepted February 1, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. Ganapathipillai, G. Laval, I. S. Hoffmann, A. M. Castejon, J. Nicod, B. Dick, F. J. Frey, B. M. Frey, L. X. Cubeddu, and P. Ferrari
CYP11B2-CYP11B1 Haplotypes Associated with Decreased 11{beta}-Hydroxylase Activity
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J. Nicod, D. Bruhin, L. Auer, B. Vogt, F. J. Frey, and P. Ferrari
A Biallelic Gene Polymorphism of CYP11B2 Predicts Increased Aldosterone to Renin Ratio in Selected Hypertensive Patients
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P. O. Lim, T. M. Macdonald, C. Holloway, E. Friel, N. H. Anderson, E. Dow, R. T. Jung, E. Davies, R. Fraser, and J. M. C. Connell
Variation at the Aldosterone Synthase (CYP11B2) Locus Contributes to Hypertension in Subjects with a Raised Aldosterone-to-Renin Ratio
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P. Mulatero, F. Rabbia, and F. Veglio
Paraneoplastic Hyperaldosteronism Associated with Non-Hodgkin's Lymphoma
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P. Mulatero, D. Schiavone, F. Fallo, F. Rabbia, C. Pilon, L. Chiandussi, L. Pascoe, and F. Veglio
CYP11B2 Gene Polymorphisms in Idiopathic Hyperaldosteronism
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