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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 4228-4231
Copyright © 1999 by The Endocrine Society

Original Studies

Mutations in CYP11B1 Gene Converting 11ß-Hydroxylase into an Aldosterone-Producing Enzyme Are Not Present in Aldosterone-Producing Adenomas

Catia Pilon, Paolo Mulatero, Luisa Barzon, Franco Veglio, Corrado Garrone, Marco Boscaro, Nicoletta Sonino and Francesco Fallo

Department of Medical and Surgical Sciences, Division of Endocrinology (C.P, L.B., M.B., N.S., F.F.), University of Padova, 35128 Padova; and the Department of Medicine and Experimental Oncology (P.M., F.V.) and the Division of Surgery (C.G.), University of Torino, 10133 Torino, Italy

Address all correspondence and requests for reprints to: Francesco Fallo, M.D., Department of Medical and Surgical Sciences, Division of Endocrinology, Via Ospedale 105, 35128 Padova, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In the human adrenal cortex, cortisol and aldosterone are synthesized by the isozymes 11ß-hydroxylase and aldosterone synthase, respectively, encoded by the 93% identical CYP11B1 and CYP11B2 genes. In vitro mutagenesis of CYP11B1 complementary DNA, resulting in the replacement of CYP11B1 codons by those encoding the corresponding amino acid residues of CYP11B2 enzyme (exon 5, Ser288Gly; exon 6, Val320Ala), yields a complementary DNA encoding a mutant enzyme with an efficient aldosterone synthase activity. Identical somatic mutations in the CYP11B1 gene in vivo would produce a gene encoding an enzyme with C18 activity and that would preserve ACTH responsiveness due to the retained 5'-promoter in the mutated CYP11B1 gene. An ACTH-responsive aldosterone synthase activity of this type is commonly seen in patients with aldosterone-producing adenomas (APA). We examined the occurrence of mutations in exons 5 and 6 of the CYP11B1 gene in APA from 10 patients with primary aldosteronism. Patients were selected on preoperative evidence of a 50% or greater plasma aldosterone decrease after short term dexamethasone trial and no aldosterone response to upright posture. DNA from adenomas was amplified by PCR using two pairs of primers spanning the regions of CYP11B1 gene, i.e. exons 3–5 and exons 6–9, where mutations could be located. Targeted regions were screened for mutations by automated sequencing of PCR products. No point mutations of the CYP11B1 gene over the two regions examined were found in APA. This argues against involvement of mutations in the pathogenesis of ACTH-responsive APA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN THE HUMAN adrenal, cortisol and aldosterone are synthesized by the isozymes CYP11B1 (11ß-hydroxylase) and CYP11B2 (aldosterone synthase), respectively. CYP11B1 catalyzes the 11ß-hydroxylation of 11-deoxycortisol to cortisol and of 11-deoxycorticosterone (DOC) to corticosterone (B) and is regulated by ACTH (1, 2). CYP11B2 catalyzes the 11ß-hydroxylation of DOC to B, the 18-hydroxylation of B to 18-hydroxycorticosterone (18-OHB), and the 18-oxidation of 18-OHB to aldosterone, predominantly under control of angiotensin II and the serum K+ concentration (1, 2, 3). CYP11B2 is exclusively expressed in the zona glomerulosa; CYP11B1 is expressed in both the zona fasciculata/reticularis and the zona glomerulosa (1, 4). The two enzymes are, respectively, encoded by the CYP11B1 and CYP11B2 genes, which are 95% identical in their coding sequence (5) and are located 40 kb apart on chromosome 8q22 (6, 7, 8, 9). In vitro experiments have shown that only 2 of the 35 amino acid differences distinguishing the CYP11B1 and CYP11B2 enzymes, i.e. Ser288Gly and Val320Ala, are responsible for the additional 18-hydroxylase and 18-oxidase activities possessed by CYP11B2, but not CYP11B1, when DOC is used as the substrate (10). Other studies have reported that Val320Ala substitution alone is sufficient to enable the CYP11B1 enzyme to catalyze limited aldosterone synthesis (11, 12). Therefore, conversion of the CYP11B1 gene by nucleotide sequences from CYP11B2, resulting in the replacement of these two amino acids by the corresponding residues of the CYP11B2 enzyme, have the potential to produce a mutant enzyme with an efficient aldosterone synthase activity. As the sequences responsible for ACTH responsiveness, assumed to be at the 5'-end of the gene, are preserved in this mutated gene, its expression should be controlled by ACTH (13, 14, 15, 16). ACTH-dependent aldosterone synthase activity is observed in the inherited hypertensive disorder glucocorticoid-remediable aldosteronism (GRA) and in hyperaldosteronism due to aldosterone-producing adenoma (APA). We hypothesized that such mutations might be involved in the formation of APAs that secrete aldosterone under the influence of ACTH. We sequenced CYP11B1 exons from a series of APA with ACTH-regulated aldosterone hyperproduction, but found no mutations in exon 5 or exon 6.


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

Ten patients (3 women and 7 men, aged 35–64 yr) with APA were studied at our centers. All were hypertensive and had hypokalemia of varying degree. PRA was suppressed and unresponsive to stimuli such as upright posture and captopril administration, and the plasma aldosterone (nanograms per dL)/PRA ratio (nanograms per mL/h) was greater than 50. The differential diagnosis between APA and hyperaldosteronism due to bilateral idiopathic adrenal hyperplasia was made by computerized axial tomography, adrenal scintiscan with [75Se]cholesterol after dexamethasone suppression, and/or aldosterone/cortisol ratio measurements in adrenal venous blood. GRA associated with adrenal tumors was excluded by either negative long PCR test or Southern blotting for chimeric gene in leukocyte DNA, as previously reported (16). The subjects were consuming a diet containing 120–150 mmol sodium and 60 mmol potassium daily for 2 weeks, and all medications were withdrawn for at least 2 weeks before the diagnostic tests. None of the patients had any other disease. The 10 patients were selected from a larger population of 23 patients with primary aldosteronism due to APA (16) based on 1) a 50% or greater supine plasma aldosterone decrease after short term dexamethasone trial (2 mg/day for 4 days; plasma cortisol suppression, i.e. <5 µg/dL, was considered an index of the dexamethasone effect), 2) a less than 30% increase or even a decrease in aldosterone after 2 h of upright posture after overnight recumbency (17). All patients underwent unilateral adrenalectomy, and the diagnosis of adenoma was surgically confirmed. Tissues were snap-frozen at -80 C until processing, and only the central portion of each tumor was studied. Four healthy adrenal glands were obtained from nephrectomized patients and used as normal controls. The adrenal cells from clinically confirmed APA were classified microscopically into the four types described by Neville and O’Hare (18). All patients gave informed consent before participating in this study.

Hormone assays

Plasma aldosterone and PRA were determined by RIA with kits purchased from Sorin Biomedical Diagnostics (Vercelli, Italy).The intra- and interassay coefficients of variation (CVs) for aldosterone were 7.9% and 9.6%, respectively; the normal range is 2–12 ng/dL supine and 5–30 ng/dL upright. The intra- and interassay CVs for PRA were 5.4% and 9.1%, respectively; the normal range is 0.4–3 ng/mL·h supine and 1.5–6 ng/mL·h upright. Plasma cortisol was measured using a RIA kit from Diagnostic Products (Los Angeles, CA). Intra- and interassay CVs were 4.1% and 5.0%, respectively; the normal range at 0800 is 5–20 µg/dL.

Molecular analysis

High mol wt genomic DNA was extracted from tumor specimens using standard methods (19). Two DNA regions encompassing exons 5 and 6 of the CYP11B1 gene were selectively amplified by PCR using specific primers as described by White at al. (20). Specifically, the exon 3–5 segment was amplified using a sense primer from intron 2 (5'-AGAAAATCCCTCCCCCCTA-3') and an antisense primer from intron 5 (5'-GACACGTGGGCGCCGTGGA-3') of CYP11B1. The exon 6–9 segment was amplified using a sense primer from intron 5 (5'-TGACCCTGCAGCTGTGTCT-3') and an antisense primer from exon 9 (5'-GAGACGTGATTAAGTTGATGGC-3') of CYP11B1. Expected fragment sizes for the two segments were 1.7 and 1.8 kb, respectively. For the exon 3–5 region, the PCR reaction was carried out using a Progene Techne PCR apparatus (UK) in 25-µL reaction volumes with 1.5 mmol/L MgCl2; 200 µmol/L each of deoxy (d)-ATP, dGTP, dTTP, and dCTP; 2 pmol of each primer; template DNA; and 1 U Taq polymerase (Promega Corp., Madison, WI). The reaction was performed using 35 cycles of 94 C denaturing for 1 min, 65 C annealing for 1 min, and 72 C extension for 3.5 min, followed by a single 10-min incubation at 72 C. For the exon 6–9 region, PCR conditions were the same, except that the annealing temperature was 60 C. For mutation analysis in exons 5 and 6 of the CYP11B1 gene, PCR products were sequenced employing the antisense primer of the exon 3–5 segment and the sense primer of exons 6–9, respectively. Sequencing was performed on an ABI PRISM 310 DNA sequencer (Perkin-Elmer Corp., Foster City, CA) using an ABI PRISM BigDye terminator Cycle Sequencing Reaction Kit with AmpliTaq DNA polymerase FS (Perkin-Elmer Corp.). Sequencing data were analyzed by the Sequencing Analysis 3.0 computer program (Perkin-Elmer Corp.). Results were compared with the CYP11B1 sequence as reported by Kawamoto et al. (21) (GenBank accession no. D16154).

The presence of a GRA-like chimeric gene was also tested in the genomic DNA extracted from all APA specimens, using both Southern analysis and the long PCR technique as previously described (22).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The preoperative data of APA patients are detailed in Table 1Go. After surgery, all patients showed normalization of serum K+ and hormone levels, with restoration of a normal aldosterone response to upright posture. Blood pressure normalization or satisfactory control after administration of low dose conventional antihypertensive drugs paralleled restoration of the electrolyte and hormonal pattern. In five patients (patients 1, 3, 4, 9, and 10), 4-day dexamethasone administration (2 mg/day) was repeated 1 yr after surgery, showing no significant change (<10%) in aldosterone levels.


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  		Table 1. Patient data: preoperative studies in 10 APA patients

 
Histologically, all APA specimens contained 50–90% of fasciculata-like cells; the nonzona fasciculata-like cells included typical zona glomerulosa type cells, hybrid cells, and small compact cells.

Aldosterone-producing tumors were sequenced for exons 5 and 6 of the CYP11B1 gene, all yielding the normal sequence. No mutations over the entire sequences of exons 5 and 6 were detected by direct DNA sequencing. No mutations were found in exons 5 and 6 of the CYP11B1 gene from the four normal adrenals used as controls. Representative analysis of DNA sequence from an APA specimen is shown in Fig. 1Go.



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  		Figure 1. Representative genomic DNA sequence analysis, of exon 5 (upper panel) and exon 6 (lower panel) of the CYP11B1 gene from an APA specimen. The nucleotide sequence predicts amino acid alignment, i.e. GCT for serine at position 288 and GTG for valine at position 320, corresponding to the normal sequence of the human CYP11B1 enzyme.

 
GRA-like chimeric gene duplications were not found in DNA from all adrenal tumors using either Southern blotting or the long PCR technique.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Aldosterone overproduction was primarily ACTH regulated in our group of patients with APA. All patients displayed a considerable decrease in plasma aldosterone after short term dexamethasone administration and no aldosterone response to upright posture. In addition, all APA specimens contained at least 50% fasciculata-like cells at histology, which might represent a cell subtype with the ability to produce aldosterone in response to minimal increments in circulating ACTH (23). We tested the possibility that hyperaldosteronism in these APAs was the result of somatic mutations of the CYP11B1 gene, leading to a mutant enzyme with aldosterone synthase activity. In our model, the preservation of ACTH-responsive 5'-promoter would account for the ACTH dependency of aldosterone overproduction seen in our patients. However, sequence analysis of DNA from our APA specimens did not show mutations of the CYP11B1 gene at position 288 in exon 5 or at position 320 in exon 6, potentially able to convert 11ß-hydroxylase to an aldosterone-producing enzyme. Furthermore, no other mutations were detected over the entire sequences of exons 5 and 6. This excludes the formation of a hybrid enzyme containing all corresponding amino acid residues encoded in the same exons of CYP11B2, which could confer on the CYP11B1 enzyme the capacity to synthesize 18-hydroxycortisol and 18-oxocortisol from an 11-deoxycortisol precursor (24). Our hypothesis is also in agreement with the simpler notion that both CYP11B1 and CYP11B2 gene transcripts and isozymes are found in APA (3, 25).

Alternate mechanisms could account for the prevalent ACTH dependency of aldosterone in APA. One possibility is the presence of somatic mutations in APA, i.e. GRA-like chimeric gene duplications, functionally equivalent to the prezygotic mutations seen in GRA. This was excluded in all APA specimens, confirming our previous findings in a different group of adenomas (22). Another possibility is that somatic mutations in the ACTH receptor gene could result in constitutive activation of the receptor in APA cells and subsequent increased aldosterone secretion despite the normal circulating levels of ACTH in this condition. However, no mutations in the ACTH receptor gene have been demonstrated to occur in APA (26, 27). Finally, as an increased expression of ACTH receptor messenger ribonucleic acid has been found in APA (28), mutations in the regulatory region (promoter) of the ACTH receptor gene may be involved. Mutations in the promoter region may abolish the binding of negative regulatory elements or, conversely, enhance binding of positive regulatory elements. In this respect, the promoter of the human ACTH receptor gene contains a binding site for steroidogenic factor-1 (29), an orphan nuclear receptor essential for its transcription (30) with a key role in the biosynthesis of steroidogenic enzymes (31, 32) that is expressed in APA (33, 34).

In conclusion, our results do not provide evidence that mutations in the CYP11B1 gene that convert 11ß-hydroxylase into an aldosterone-producing enzyme are present in APA. This argues against a CYP11B1-mutated enzyme as the cause of ACTH-regulated aldosterone overproduction in these tumors.


   Acknowledgments
 
The authors thank Dr. L. Pascoe (Fondation Jean Dousset CEPH, Paris, France) for helpful advice.

Received March 16, 1999.

Revised June 30, 1999.

Accepted August 3, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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