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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 611-615
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

Somatic Mutations of the Angiotensin II (AT1) Receptor Gene are Not Present in Aldosterone-Producing Adenoma1

Eleanor Davies2, Alain Bonnardeaux, Pierre-François Plouin, Pierre Corvol and Eric Clauser

INSERM U-36, Collège de France, Paris, France

Address all correspondence and requests for reprints to: Dr. Eric Clauser, INSERM U-36, Collège de France, 3 rue d’Ulm, 75005 Paris, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Angiotensin II stimulates aldosterone secretion from the adrenal zona glomerulosa and mediates most of its biological effects via G protein-coupled type 1 angiotensin II receptors (AT1). A number of G protein-coupled receptors are constitutively activated as a result of somatic mutations in the gene encoding the protein. It is, therefore, possible that primary hyperaldosteronism caused by an aldosterone-producing adenoma (APA) may be the result of constitutive activation of the AT1 receptor. The 1.1-kilobase coding region (exon 5) of the AT1 receptor gene was analyzed in APA and normal adrenal tissue for the presence of mutations using single stranded conformational polymorphism and sequencing techniques. In 17 APAs, no functional mutations were found that could account for the observed pathophysiology. However, three silent polymorphisms were detected in regions encoding the second extracellular loop, the intracellular arm preceding the COOH terminal, and the 3'-untranslated region. In conclusion, somatic mutations in the coding region of the AT1 receptor gene do not appear to play a role in primary hyperaldosteronism caused by an APA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRIMARY hyperaldosteronism is characterized by hypertension, hypokalemic alkalosis, suppressed PRA, low angiotensin II levels, and elevated aldosterone secretion. This may be caused by bilateral adrenal hyperplasia or glucocorticoid-suppressible hyperaldosteronism. However, in two of three cases, this is caused by an aldosterone-producing adenoma (APA; Conn’s syndrome) (1), and it is this particular form of primary hyperaldosteronism on which our studies are based.

Angiotensin II is the principal hormone controlling mineralocorticoid secretion by the adrenal zona glomerulosa. It is also a potent vasoconstrictor and, therefore, plays an important role in sodium and blood pressure homeostasis (2). Its actions are mediated by two types of membrane-bound glycoprotein receptor. In man, the type 1 (AT1) receptor is located predominantly in the vascular system, liver, kidney, and adrenal cortex, and the type 2 (AT2) receptor is located in the uterus, brain, and adrenal medulla of the rat (3). The AT1 receptor mediates most of the known physiological actions of angiotensin II, and the gene has been cloned in human and several other mammalian species (4, 5, 6, 7, 8). The human AT1 receptor gene is located on chromosome 3q22 (9) and is composed of five exons and four introns spanning an area greater than 55 kilobases (kb). The entire open reading frame is contained in exon 5 and is approximately 1.1 kb (10). The receptor is G protein coupled and is predicted to have seven-transmembrane domain (7-TMD) topography (6).

There is accumulating evidence from other 7-TMD, G protein-coupled receptors to suggest that mutations can result in constitutive activation, which may be responsible for a number of genetic or acquired endocrine disorders. For example, in hyperfunctioning thyroid adenomas, somatic mutations have been found in the nucleotides encoding the third intracellular loop and a number of other areas of the 7-TMD structure, which cause activation of adenylyl cyclase when tested in vitro (11, 12, 13). Similarly, a mutation in the sixth TMD of the LH receptor is believed to be responsible for male precocious puberty (14). Mutations in the first intracellular loop and the second TMD of the murine {alpha}MSH receptor result in darkened coat color (15). In vitro studies, mutating various residues in the third intracellular loop of the {alpha}- and ß-adrenergic receptors, have also resulted in constitutive activation (16, 17, 18). Therefore, somatic mutations can result in permanent activation of G protein-coupled receptors, and in some instances, these can then behave as protooncogenes.

In the most common form of primary hyperaldosteronism caused by an APA, aldosterone secretion is no longer under normal regulation by angiotensin II. This may be due to a defect in the angiotensin receptor or its signal transduction system. In particular, a somatic mutation in the AT1 receptor gene may constitutively activate the receptor, thereby increasing aldosterone secretion. To test this hypothesis, we analyzed the AT1 receptor gene in APA for the presence of functional mutations using PCR/single strand conformational polymorphism (SSCP) (19) and direct sequence analysis.


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

The clinical features of the patients (10 women and 7 men) with primary hyperaldosteronism resulting from an APA are shown in Table 1Go. Diagnosis of an APA was based on varying criteria, including hypertension, hypokalemia of 3.7 mmol/L or less, supine plasma aldosterone greater than 150 pg/mL, active renin (standing) less than 15 pg/mL, aldosterone/renin ratios, computed tomographic scanning, and/or unilateral elevation of adrenal venous aldosterone secretion (20). After surgery, adenoma tissue was stored in liquid nitrogen until DNA/ribonucleic acid (RNA) extraction. Three healthy adrenal glands were obtained from nephrectomy patients.


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  		Table 1. Clinical features and pathology of patients with aldosterone-producing adrenal adenomas

 
Extraction of DNA/RNA from adrenal tissue

Genomic DNA was extracted from the tissue by phenol-chloroform extraction and isopropanol precipitation (21) and resuspended in TE (Tris 10 mM, EDTA 1 mM, pH 7.5), (15 ng/µL). Total RNA was extracted from some tissue using guanidine thiocyanate (22), resuspended in diethylpyrocarbonate-treated water (1 µg/µL), and stored at -70 C. First strand DNA was synthesized from 1–2 µg total RNA in a final volume of 20 µL, containing 0.2 µg oligo-deoxythymidine primer, 0.5 mmol/L of each deoxy (d)-NTP, 50 mmol/L Tris, 75 mmol/L KCl, 10 mmol/L dithiothreitol, 3 mmol/L MgCl2, BSA (2%), 2 U RNAsin, and 200 U Moloney murine leukemia virus reverse transcriptase (Life Technologies, Grand Island, NY). After 1 h at 37 C, the reaction was terminated by heating to 95 C for 2 min.

Identification and detection of AT1 receptor gene polymorphisms

Six overlapping fragments (~300 bp) of AT1 exon 5 were amplified by PCR using the primers shown in Table 2Go. PCR was carried out in a total volume of 25 µL, using 50–200 ng DNA, 50 mmol/L KCl, 0.01% gelatin, 5 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl2, 100 µmol/L dNTPs, 1.0 U Taq polymerase (Boehringer Mannheim, Indianapolis, IN), and 10 pmol of each primer end labeled with [{gamma}-32P]dATP using T4 polynucleotide kinase. Thirty cycles of amplification were performed, consisting of denaturation for 30 s at 94 C and annealing/elongation for 20 s at 56 C. An initial denaturation stage was carried out at 94 C for 4 min.


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  		Table 2. Primer pairs used for amplification of the human angiotensin II (type 1) receptor gene

 
The PCR products were digested using the restriction enzymes shown in Table 2Go. The digests were then diluted 2-fold in a solution containing 95% formamide, 10 mmol/L ethylenediamine tetraacetate, 0.05% bromophenol blue, and 0.05% xylene cyanol and analyzed by SSCP (19). After denaturation at 94 C for 4 min, 4 µL were loaded onto a 5% nondenaturing acrylamide gel (49:1, polyacrylamide-bisacrylamide) in the presence or absence of 5% glycerol and 0.5 x TBE (89 mM Tris-borate, 89 mM boric acid, EDTA 0.2 mM). Gels with glycerol were run at room temperature, and those without glycerol were run at 4 C. PCR products were visualized by autoradiography.

Direct sequencing

Sequencing was carried out to characterize the electrophoretic variants detected by SSCP and verify that some mutations had not gone undetected using the SSCP conditions described. A fragment of the AT1 gene was amplified using the primers in Table 2Go. The PCR products were purified by low melting point agarose gel electrophoresis and eluted using GeneClean (BIO 101, Vista, CA). Cycle sequencing was carried out on both strands using a Circumvent Kit (New England Biolabs, Beverly, MA) and an internal primer end labeled with [{gamma}-32P]dATP using T4 polynucleotide kinase.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The entire open reading frame and part of the 3'-untranslated region of the AT1 receptor gene were analyzed. No mutations were detected with primer pairs 1 and 2, which span nucleotides -42 to 550. SSCP analysis of nucleotides 423–766 is shown in Fig. 1Go, which shows representative results from 10 APAs (Table 1Go, patients 1–10) and 3 healthy adrenal glands. The band shown is the 204-bp fragment liberated after digestion with Sau3A. There are 2 electrophoretic variants, present in either homozygous or heterozygous form. Sequencing revealed a T to C transition at nucleotide 573 of the human AT1 receptor gene. Lanes 4 and 7 of the APA samples represent individuals who are homozygous for the wild-type (TT) and transition (CC), respectively, whereas lane 1 represents an individual who is heterozygous (TC). All 3 controls (healthy adrenal glands) were heterozygous. Nucleotide T573 is part of a codon for a leucine residue, situated in the second extracellular loop immediately before the fifth TMD (10). The T to C transition does not alter the encoded amino acid. This silent transition was observed in DNA from APA, healthy adrenal gland, and blood samples (not shown).



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  		Figure 1. SSCP analysis of PCR-amplified DNA fragments encoding bp 423–766 of the human angiotensin (AT1) receptor in 10 APAs and 3 healthy adrenal glands. The band shown is the 204-bp fragment liberated by digestion with Sau3A. Nondenaturing acrylamide (5%) gel electrophoresis was carried out at room temperature at 30 watts for 4–5 h in the presence of 5% glycerol and 0.5 x TBE.

 
Nucleotides 661-1000 encode the third intracellular loop of the AT1 receptor, an area considered to be important in constitutive activation. However, SSCP analysis of this region using primer pair 4 did not detect any mutations, and this is illustrated in Fig. 2Go, which again shows representative results from 10 APAs (Table 1Go, patients 1–10) and 3 healthy adrenal glands. The band shown represents the 200-bp fragment liberated by FokI digestion. No electrophoretic variants were detected in the other band (140 bp) liberated by the digestion. This result was confirmed in 4 APA samples by sequencing.



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  		Figure 2. SSCP analysis of PCR-amplified DNA fragments encoding bp 661-1000 of the human angiotensin (AT1) receptor in 10 APAs and 3 healthy adrenal glands. The band shown is the 200-bp fragment liberated by digestion with FokI. Nondenaturing acrylamide (5%) gel electrophoresis was carried out at room temperature at 30 watts for 4–5 h in the presence of 5% glycerol and 0.5 x TBE.

 
Analysis of nucleotides 847-1134 with primer pair 5 revealed an A to G transition at nucleotide 1062 (data not shown). This nucleotide is part of the codon for a proline residue located in the long intracellular arm immediately before the carboxyl-terminal. Again, this transition does not alter the amino acid and was observed in DNA from APA, healthy adrenal gland, and blood samples, although none of the samples analyzed in this study was homozygous (GG) for the transition.

Finally, analysis of the 3'-flanking region using primer pair 6, revealed an A to C transition at nucleotide 1166, 82 bp from the stop codon (data not shown). This did not alter a potential polyadenylation site or any destabilization signal. Again, this was observed in DNA from tumor, healthy adrenal gland, and blood samples, although none of the samples analyzed in this study was homozygous (CC) for the transition.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Angiotensin II plays a key role in blood pressure and sodium homeostasis. Most of its known physiological actions are mediated by AT1 receptors, which belong to the G protein-coupled, 7-TMD superfamily (23). A number of other receptors belonging to this family are constitutively activated as a direct result of conformational changes caused by spontaneous somatic mutations in the genes encoding them; some examples are outlined in the introduction (24).

An APA is the most common cause of primary hyperaldosteronism. In adrenal adenoma tissue, angiotensin binds predominantly to AT1 receptors, although AT2 receptors are present (25). As angiotensin II is the main regulator of aldosterone secretion, it is possible that a somatic mutation in the AT1 receptor gene could result in constitutive activation of the receptor and subsequent increased aldosterone secretion despite the low circulating levels of angiotensin II in this condition.

To test this hypothesis, we extracted DNA or RNA from 17 APAs and 3 healthy adrenal glands and analyzed the coding exon (exon 5) of the AT1 gene by SSCP (19) and direct sequencing. No functional mutations were detected in either the third intracellular loop or any other area of the 7-TMD structure that alter the amino acid composition of the AT1 receptor. However, three silent polymorphisms were identified in both normal and pathological tissue: a T to C transition at nucleotide 573, which forms part of the codon for a leucine residue in the second extracellular loop; an A to G transition at nucleotide 1062, which encodes a proline residue in the intracellular arm proceeding the COOH terminal; and an A to C transition at nucleotide 1166 in the 3'-untranslated region of the gene, which does not appear to alter a potential messenger RNA (mRNA) polyadenylation or destabilization signal. Previous work from our group has shown a significant increase in the A1166 polymorphism in hypertensive subjects, suggesting that although not functional, it may be in linkage disequilibrium with another, as yet unidentified, functional variant (26).

Although there are naturally occurring polymorphisms in exon 5 of the AT1 receptor gene in APA, there are no functional somatic mutations that could explain the elevated levels of aldosterone. The sensitivity of SSCP for analyzing DNA fragments of ~150 bp is more than 95%, and using two different electrophoretic conditions minimizes the risk of nondetection (27). However, it is possible that we failed to identify some variants due to these technique limitations. We attempted to eliminate this possibility in four of the APA samples by carrying out complete sequence analysis.

Although the results are negative, they do not completely exclude a role for the AT1 receptor in this particular form of primary hyperaldosteronism. It is possible that the regulatory region (promoter) of the gene may be involved. This region has been cloned and characterized by ourselves and others (28, 29) and is situated 2.5 kb upstream of exon 1. Although we did not study AT1 receptor gene expression in our patients, studies by other groups have shown a 2- to 8-fold increase in AT1 mRNA in adenoma tissue and a 1.7- to 2.5-fold increase in AT1 mRNA in leukocytes from patients with APA (30, 31, 32). This increased gene expression can be interpreted in two ways. Firstly, mutations in the promoter region of the gene may abolish the binding of negative regulatory elements or, conversely, enhance binding of positive regulatory elements. However, it is unlikely that an increase in receptor expression alone can increase aldosterone secretion, as circulating levels of angiotensin II remain low, unless this was accompanied by an increase in receptor affinity. Some groups have reported expression of a high affinity angiotensin II-binding site in adrenal adenoma (25), whereas others have reported no change in affinity (33). Ligand binding studies and SSCP analysis of the promoter region are required to detect mutations that could result in overexpression of a high affinity receptor.

The second and most likely explanation for the increased AT1 mRNA in APA is that it is secondary to the increased aldosterone levels. It has been shown that AT1 receptors are regulated at the transcriptional level by angiotensin II itself, dexamethasone, and aldosterone (34, 35, 36, 37, 38, 39). Therefore, the high levels of aldosterone produced by the adenoma may account for the increase in AT1 receptor expression in the adenoma tissue and leukocytes. This hypothesis is supported by the fact that surgical removal of the tumor decreases AT1 mRNA expression in the leukocytes (32).

In addition to the promoter, other regulatory regions in the AT1 gene may be involved in hyperaldosteronism. The AT1 receptor gene is composed of five exons, and a number of splice variants have been identified (10, 29). The entire coding sequence is contained within exon 5, and the exact function of the other exons remains unclear. Our studies suggest that exons 1 and 2 may inhibit translation due to their hairpin-like secondary structure. In addition, exon 4 contains a start codon that results in an amino-terminal extension of 35 amino acids encoding a longer protein, which may be a novel receptor isoform (29). No mutations were detected in exon 4 in our studies on APA (data not shown). The other three exons remain to be studied.

In summary, our experiments do not provide any evidence that there is an abnormality in the AT1 receptor gene in APA. Although the AT1 receptor gene remains a likely candidate in the pathogenesis of this form of primary hyperaldosteronism, further experiments are required to completely elucidate its role.


   Footnotes
 
1 This work was supported by INSERM Grant 493015 for the COMETE (Cortico et Medullosurénale: Etude des Tumeurs Endocrines) Network, Programme Hospitalier de Recherche Clinique Grant AOM95201, La Fondation pour la Recherche Medicale (to E.D), and the Canadian Medical Research Council (to A.B). Back

2 Current address: Medical Research Council, Blood Pressure Group, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, Scotland, United Kingdom. Back

Received July 16, 1996.

Revised October 7, 1996.

Accepted October 9, 1996.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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