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Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat (P.S., Y.K., M.-H.L., E.P., M.L., M.-C.Z.), 75018 Paris, France; Division of Nephrology, Robert Debré Hospital (A.-L.L.), 75019 Paris, France; Division of Nephrology (R.S., P.N.) and Division of General Pediatrics (V.A.), Department of Pediatrics, Necker-Enfants Malades Hospital, 75015 Paris, France; Division of Endocrinology (P.S., D.A.), Department of Medical and Surgical Sciences, University of Padova, 35100 Padova, Italy; Division of Pediatric Endocrinology (U.K.), Department of Pediatrics, Ludwig Maximilian University of Munich, 80337 Munich, Germany; Institute G. Gaslini (E.D.B., A.N.), Division of Pediatrics I, 16148 Genova, Italy; Department of Endocrinology (A.M.F., P.L.), Niguarda Ca’Granda Hospital, 20162 Milan, Italy; Henri Mondor Hospital (A.R.), 15002 Aurillac, France; Centro Diagnostico Italiano (M.B.), 20147 Milan, Italy; Department of Internal Medicine (M.C.), Chair of Endocrinology, University Roma "Tor Vergata," 00133 Rome, Italy; Division of Pediatrics (C.D.G.), Orsay General Hospital, 91405 Orsay, France; and Division of Neonatology (V.P-Y., J.P.C.), Le Havre Hospital, 76083 Le Havre, France
Address all correspondence and requests for reprints to: Maria-Christina Zennaro, M.D., Ph.D., Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, B. P. 416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France. E-mail: zennaro{at}infobiogen.fr.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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1000-fold higher levels than mineralocorticoids) into inactive 11-dehydro cogeners (6). In addition to epithelial target tissues, aldosterone exerts important effects in the cardiovascular and in the central nervous system. It has been shown that aldosterone plus salt can lead to the development of cardiac hypertrophy and fibrosis in rats (7) and that intracerebroventricular infusion of aldosterone raises blood pressure (8). Most importantly, there is evidence for a major clinical benefit of aldosterone antagonists in reducing the morbidity and mortality in patients affected by cardiac failure (9). Finally, recent data demonstrate that adipose tissue is a new target tissue for aldosterone, which is capable of regulating cell differentiation and thermogenesis (10, 11, 12, 13), thus indicating a role for mineralocorticoids in the regulation of energy balance.
The human MR (hMR) gene spans over approximately 400 kb and is composed of ten exons (14). Exon 2 contains the translation start site and codes for the amino-terminal part of the receptor; two small exons, 3 and 4, code for the DNA binding domain (DBD) and 5 exons code for the ligand binding domain (LBD). Alternative transcription of two 5'-untranslated exons generates two mRNA isoforms, hMR
and hMRß, which are coexpressed in aldosterone target tissues (15). Characterization of hMR regulatory regions has shown that hMR gene expression is controlled by complex regulatory mechanisms involving distinct tissue-specific utilization of two alternative promoters, which are under differential hormonal control (16, 17). In addition to the hMR and hMRß mRNA isoforms, various splice variants exist in rat and human, which code for different hMR proteins. These include a variant possessing an insertion of four residues between the two zinc fingers of the DBD (18) and a C-terminal truncated MR variant with no ligand-dependent transactivation capacity and which is incapable of modulating wild-type MR activity (19). We have recently identified a new hMR isoform, hMR
5,6, resulting from an alternative splicing event skipping exons 5 and 6 of the hMR gene (20). This variant, which lacks the entire hinge region and ligand binding domain, is expressed in several human tissues and acts as a ligand-independent transactivator. Coexpression of hMR5,6 with hMR or human glucocorticoid receptor, increases their transactivation potential at high doses of hormone, suggesting that this new variant might play a role in modulating corticosteroid effects in target tissues.
Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive associated with hyponatriemia, hyperkalemia, and metabolic acidosis, in the presence of extremely high values of plasma renin and aldosterone (21). Different modes of inheritance have been observed. In the autosomal dominant form of PHA1, mineralocorticoid unresponsiveness seems restricted exclusively to the kidney, whereas subjects affected by the autosomal recessive form, display a generalized resistance and a more severe form of PHA1 (22, 23). The sporadic form of the disease is a mild form resembling to the autosomal dominant form of PHA1. Therapy consists of sodium supplementation, which can be discontinued after a variable period of time in the autosomal dominant form and in sporadic cases, which present a favorable evolution of the disease. However, high aldosterone levels may persist even after normalization of the clinical picture. In contrast, in the recessive form of PHA1, life-long supplementation with high doses of salt is required, and patients are subject to recurrent life-threatening episodes of salt loss. Molecular mechanisms underlying these two clinical entities have been resolved in recent years. Recessive PHA1 is due to homozygous mutations in the three subunits of the ENaC, whereas in autosomal dominant and sporadic PHA1 different heterozygous inactivating mutations have been identified in the hMR gene (24). These include a nonsense mutation at position 1831 (C1831T, R537*) and two single base pair deletions (G1226, T1597) introducing frameshift mutations leading to premature stop codons. A single base pair deletion in the intron 5 donor splice site changes the consensus sequence, suggesting aberrant splicing. Another frameshift mutation (InsC2871) was detected in a sporadic case of PHA1 (25), introducing a new 54-amino acids into the MR C terminus, most likely changing the conformation of the ligand binding pocket, thus impairing ligand binding capacity. Only one missense mutation has been identified to date. A heterozygous substitution of proline for leucine at codon 924 (L924P) was described in a Japanese family (26). This mutation strongly reduces hMR-mediated transactivation of a reporter gene.
The aim of our study was to identify and to characterize new hMR mutations in a large cohort of patients affected by autosomal dominant or sporadic PHA1. Analysis of the hMR in 14 unrelated kindreds revealed six new mutations, including three missense mutations, which differently affect protein structure and function.
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Patients and Methods |
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A total of 15 symptomatic patients from 14 families from 12 different centers in France, Italy, and Germany have been studied. In each family, the index patient presented in early infancy (from 1 wk to 5 months) with poor weight gain, failure to thrive, dehydration, or vomiting. The diagnosis of PHA1 had been made by serum concentrations of aldosterone and PRA and electrolytic measurements. All patients were treated by sodium supplementation and/or ion exchange resins throughout early infancy, in most patients sodium replacement therapy could be discontinued in later childhood. In six kindreds, a familial history of elevated salt appetite, salt loss, or vomiting in infancy, and modification of biochemical parameters indicated a dominant transmission of PHA, whereas four cases appeared to be sporadic. No families were consanguineous, although in two cases, parents originated from a small isolated community. Five children were born preterm; pregnancy was complicated by hydramnios in four cases, three of which were associated with preterm delivery. Diagnosis of PHA1 was made at 1 wk of age in seven cases, whereas the others were diagnosed between months 1 and 5 of life. In four cases, PHA1 was associated with other pathologies, and one proband (PHA1–9) died at age 45 d from severe dehydration and shock. The clinical and biochemical results for the PHA1 probands are summarized in Table 1
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Blood samples for genetic studies were taken after informed consent from the patients or their parents. DNA was prepared from white blood cells using QIAamp DNA Blood Midi kit (QIAGEN, Valencia, CA). All hMR coding exons and the intron exon flanking regions were amplified using 11 pairs of primers; primer sequences are available upon request. For each PCR experiment, 100 ng DNA were amplified in the presence of 1.5 or 3 mM MgCl2, 400 nM of each primer, 200 µM deoxynucleotide triphosphates, and 1.25 U Platinum Taq DNA polymerase (Invitrogen, Paisley, UK). Reaction parameters were as follows: 1 cycle of 5 min at 94 C, 1 min 51–62 C, and 1 min at 72 C, followed by 30–35 cycles at 94 C for 45 sec, 51–62 C for 45 sec, and 72 C for 45 sec. PCR was concluded by 7 min at 72 C. Products were separated on 2% agarose gel and visualized by ethidium bromide staining.
Before sequencing, PCR products were purified using the QIAquick-spin purification kit (QIAGEN, Valencia, CA). Direct sequencing of PCR products was performed using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosytems, Foster City, CA) on an ABI PRISM 3700 DNA Analyzer.
Site-directed mutagenesis
Each mutation was created by site-directed mutagenesis using the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA) on the recombinant pcDNA3-hMR plasmid containing a 3 kb hMR XmaIII-AflII fragment inserted into pcDNA3 (Invitrogen; Ref. 27). The following sense primers were used together with their corresponding antisense oligonucleotide:
G2119A-S 5'-CTTCAAAAGAGCAGTGGAAAGGCAACACAACTATTTATG-3'
Ins1354T-S 5'-CCCTTTTCCTAAGACTTGAGGAAGTAGAGAGTG-3'
Del8bp537-S 5'-ACTGTAGCTGAGTCCATATATGGATTCTGTAAGA G-3'
A2549G-S 5'-CGCTTAGCAGGCAAACGGATGATCCAAGTCGTG-3'
T3158C-S 5'-GGGAACGCCAAGCCGCCCTACTTCCACCGGAAG-3'
The desired mutations were identified by directed sequencing. After identification of mutated clones, these were entirely sequenced to check for the absence of random mutations. hMR fragments were subsequently excised with HindIII and NotI and subcloned into a new pcDNA3 expression vector.
Cell culture and transfection procedures
Rabbit RCSV3 cells derived from kidney cortical collecting duct (28) were kindly provided by Dr. P. Ronco (Hôpital Tenon, Paris, France). Cells were grown in a defined medium composed of DMEM-HAM’s F12 supplemented with 5 µg/ml insulin, 5 µg/ml transferrin, 2 mM glutamine, 100 UI/ml penicillin, 100 µg/ml streptomycin, 20 mM HEPES, 50 nM sodium selenate, 50 nM dexamethasone, and 2% charcoal-stripped fetal calf serum. The cells were seeded in six-well plates at a density of 3 x 105 cells per well at least 6 h before transfection in fresh medium without any added steroid. For all transfection experiments, RCSV3 cells were used between passages 30 and 40.
Cells were transfected by the calcium phosphate method with 0.3 µg of plasmids pcDNA3-hMR, pcDNA3-R633, pcDNA3-R776, pcDNA3-P979, pcDNA3-8bp537, and pcDNA3-insT1354, coding for the wild-type and mutated hMRs, in the presence of 0.8 µg of a mouse mammary tumor virus (MMTV)-luciferase reporter construct (pF31luc, gift from Dr. H. Richard-Foy), as previously described (16). Cotransfection of 0.16 µg pSVßgal (CLONTECH Laboratories, Inc., Palo Alto, CA), a plasmid encoding for ß-galactosidase, was performed to normalize for transfection efficiencies. The day after transfection, cells were rinsed with PBS and steroids were added for 24 h. The cells were rinsed twice with cold PBS and lysed in 25 mM glycyl-glycine at pH 7.8, 1 mM EDTA, 1 mM dithiothreitol, 8 mM MgSO4, 1% Triton X-100, and 15% glycerol. Cellular extracts were assayed for luciferase and ß-galactosidase activities (16). Results were standardized for transfection efficiency and expressed as the ratio of luciferase activity over ß-galactosidase activity in arbitrary units. Aldosterone was purchased from Sigma (St. Louis, MO).
In vitro transcription and translation
In vitro transcription and translation were accomplished using the TNT Quick Coupled Transcription/Translation system (Promega Corp., Madison, WI) following the manufacturer’s protocol. Recombinant plasmids coding for wild-type or mutated hMR were used as a template for transcription with T7 polymerase, followed by translation with [35S]-methionine (1000 Ci/mmol, Amersham, Les Ulis, France). Radioactive products were analyzed on 7.5% and 15% SDS-PAGE gel. Cold methionine was used for translation of proteins used in binding studies.
Aldosterone binding assays
Reticulocyte lysates containing the wild-type or mutant hMRs were diluted 4-fold with TEGWD buffer (20 mM Tris-HCl, pH 7.4; 1 mM EDTA; 10% glycerol; 20 mM sodium tungstate; and 1 mM dithiothreitol) and incubated for 4 h at 4C with 10 nM [3H] aldosterone (Amersham Pharmacia Biotech, Little Chalfont, UK; specific activity, 1.92 TBq/mmol) alone or in the presence of a 100-fold excess of unlabeled steroid to determine specific and nonspecific binding. Bound (B) and unbound (U) steroids were separated by the dextran-charcoal method: 25 µl lysate were stirred for 5 min with 50 µl 4% Norit A, 0.4% Dextran-T70 in TEGWD buffer, and centrifuged at 4500 x g for 5 min at 4 C. Bound steroid was measured by counting the radioactivity of the supernatant in a liquid scintillation spectrometer (LKB, Rockville, MD) after adding 5 ml OptiPhase HiSafe (counting efficiency 
50%).
Aldosterone binding characteristics were calculated by Scatchard plot analysis using increasing concentrations of [3H] aldosterone (1–100 nM). Bound (B) and unbound (U) steroids were separated by the dextran charcoal method. The change in B as a function of U was analyzed as previously described (29) and the dissociation constant at equilibrium (Kd), the maximum number of sites, and the constant of the nonspecific binding were calculated.
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Results |
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Six different heterozygous mutations were detected in 14 kindreds (Fig. 1). In family PHA1–2, insertion of a thymine at nucleotide position 1354 (insT1354, numbering corresponds to the published hMR sequence [Ref. 3 ; to convert to GenBank sequence numbering (HUNNCR), subtract six nucleotides] in exon 2 introduces a frameshift resulting in a premature stop codon at amino acid position 378. This mutation was found in both twins and in the affected brother, as well as in their mother. Another frameshift mutation in exon 2, del8bp537, due to deletion of eight nucleotides at position 537 in family PHA1–12, was found in the proband, its affected sister and in their mother. The frameshift resulted in a truncated protein with eight novel residues after Ser104, followed by a premature stop codon. One nonsense mutation in exon 4, C2157A, found in the index case of family PHA1–15, changes cysteine 645 to a stop codon in the second zinc finger of the hMR DBD. Three different missense mutations change the amino acid sequence of the receptor. In family PHA1–3, an A2549G substitution in exon 5 changes glutamine 776 to arginine (Q776R). The mutation was found in the index case, her mother, and in the maternal grandfather’s DNA. Mutation of the last nucleotide of exon 3, guanine 2119, to alanine in family PHA1–13 replaces glycine 633 with an arginine (G633R); this mutation was found in two brothers and all of their offspring. Finally, a T3158C substitution in exon 9 found in the index case and her mother in family PHA1–4 changes leucine 979 to proline (L979P). All of the missense mutations affect highly conserved residues of either the DBD (G366R) or the LBD (Q776R, L979P; Fig. 2), which are identical in the glucocorticoid, progesterone, and androgen receptor, indicating that these amino acids may be involved in specific and important protein functions.
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In vitro transcription/translation experiments were performed to study the protein and binding characteristics of hMR harboring the missense mutations R633, R776, and P979. Insertion and deletion mutants insT1354 and del8bp537 were also translated in vitro to analyze the resulting hMR fragments. As presented in Fig. 3, all hMR missense mutants were translated with the same efficacy as wild-type hMR and generated proteins of the expected size of approximately 110 kDa (Fig. 3A). Mutant insT1354 also generated a protein with the expected molecular mass of approximately 40 (Fig. 3, A and B). The expected protein mass for mutant del8bp537 is approximately 12; however, no band at this size was present on our SDS-PAGE gels (Fig. 3B), suggesting that the mRNA or the translation product are unstable. In contrast, a faint new band was visible at approximately 95 kDa, which could correspond to an N-terminal truncated hMR lacking the first 108 amino acids, due to the use of an alternative translation initiation site at Methionine 109.
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). Whereas R633 retained the aldosterone binding capacity of the wild-type receptor, R776 displayed only 30% of maximal aldosterone binding and mutant P979 completely lost aldosterone binding (Fig. 4A). The aldosterone binding characteristics of the mutant hMRs expressed in vitro was further characterized by measuring the Kd (Fig. 4B). Aldosterone bound to R633 with the same affinity than that observed for wild-type hMR under our experimental conditions, whereas the Kd of R776 for aldosterone was approximately 10-fold lower. The maximum number of sites was comparable between the three receptors.
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Transcriptional activation by mutant hMRs
The ability of mutant hMR proteins to activate transcription of a reporter gene was tested by transient transfection assays in rabbit renal RCSV3 cells. Expression vectors for wild-type and mutant receptors were transfected together with an MMTV-luciferase reporter plasmid in the presence of increasing concentrations of aldosterone (10-11 M to 10-7 M). As shown in Fig. 5A, aldosterone increased transactivation by the wild-type hMR in a dose-dependent manner, with a plateau reached at 10-9 M aldosterone. Maximal luciferase activity induced by R633 and R776 was, respectively, 60% and 80% of that observed with hMR at 10-7 M aldosterone and the dose-response curves never reached a plateau. The ED50 of hMR induced transactivation was approximately 5 x 10-11 M and no difference was observed for R633 (Fig. 5B), consistent with the aldosterone binding characteristics of this mutant measured by Scatchard plot analysis. In contrast, substitution of glutamine 776 by arginine induced a shift in the dose-response curve of the aldosterone-induced luciferase activity toward higher concentrations with an ED50 value of approximately 10-8 M. As shown in Fig. 5C, mutant P979 was not able to activate transcription from an MMTV promoter in the presence of aldosterone, as it was the case for the residual hMR fragments generated by the insertion or deletion mutants insT1354 and del8bp537.
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). At increasing concentrations of R633, this effect was no more present. The two other hMR mutants, R776 and P979, in contrast, behaved as dominant negative modulators of hMR activity, reducing maximal activation by 60% when they were present at 5-fold higher concentrations than the wild-type receptor. Given the equivalent expression levels of all receptors observed in in vitro transcription/translation assays and binding studies (Figs. 3
and 4), it appears that, at an equimolar ratio of wild type over mutated hMRs, likely to occur in vivo, wild-type receptor activity was enhanced by R633 (164 ± 10.48%, mean ± SEM, P < 0.001), not significantly modified by R776 and inhibited by P979 (69.53 ± 4.82%, mean ± SEM, P < 0.01) Finally, we have also investigated whether truncated hMR fragments resulting from insT1354 and del8bp537 influence wild-type receptor activity. No significant modification of hMR-induced transactivation was observed with these mutants (data not shown).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The pathogenic mechanism underlying the development of clinical and biochemical stigmata of PHA1 in our patients was investigated by analyzing the effects of mutant receptors on the activity of wild-type hMR. Our data demonstrate that, whereas mutant R776 does not significantly modulate hMR activity at equimolar concentration, which are expected to be present in PHA1 patients, L979P not only is a loss-of-function mutation but possesses a dominant negative effect on hMR-induced transactivation. This may be due either to formation of less active heterodimers with wild-type receptors or to competition for DNA binding elements (34). In contrast, mutant R633 increases activity of hMR in our experiments, indicating that in vivo expression of the mutated protein is incompatible with PHA1. Therefore, we raise the hypothesis that this particular mutation, given its localization on the very last nucleotide of exon 3, may either affect a consensus splice site or disrupt an exonic splicing enhancer, thus generating incorrectly spliced transcripts that eventually might undergo mRNA degradation (35). Indeed, mutations altering existing or creating new splice sites account for 15% of point mutations associated with human genetic diseases (36) and additional splicing mutations resulting from exonic splicing enhancer disruption may even be more prevalent. Unfortunately, patient’s RNA was not available for further studies to verify this hypothesis. The mutation is not a polymorphism because it segregates with the disease in family PHA1–13 and is not present in 250 chromosomes of unrelated subjects. Finally, the incapacity of mutants insT1354 and del8bp537 to activate transcription in response to aldosterone and the absence of effect on hMR-induced transactivation indicate that PHA1 in families harboring these mutations probably results from haploinsufficiency.
Several different hMR mutations leading to PHA1 have been described (24, 25, 26). However, as in previous reports, several patients from our cohort do not present mutations in the coding exons of hMR and in the intron/exon splice junctions. Given the large size of the gene, gross deletions could not be completely excluded by SNP analysis of a limited number of polymorphic marker of the hMR gene in affected families (data not shown; Refs. 37, 38 ; and Sartorato, P., and M.-C. Zennaro, unpublished results). When using for PHA1 diagnosis strict parameters, i.e. hyponatremia, hyperkalemia, elevated plasma aldosterone, and/or renin levels, we found hMR mutations in 71% (5 of 7) of our autosomal dominant cases and 30% of sporadic cases (1 of 3). Given the size of untranslated hMR sequences, which represent 50% of the mRNA, the probability that the remaining 30% of autosomal dominant cases possess mutations in these regions is quite high, implying that analysis of untranslated hMR exons (1, 1ß, part of exon 9) and eventually promoter regions should be included in mutation screening in PHA1 patients, at least in those cases in which familial transmission has clearly been established. In two cases (PHA1–5 and PHA1–11), although no familial consanguinity was present, common origin from a small isolated village or community does not allow one to exclude that parents are far cousins. In this case, autosomal recessive PHA with a mild phenotype associated with mutations in the ENaC cannot be excluded. Finally, a certain number of patients, although diagnosed and treated as PHA1, might have possibly been affected by a different pathology, underlining the importance of a precise clinical and biochemical evaluation. It might also be possible that other proteins participating in the regulation of sodium transport in the distal nephron are involved in the pathogenesis of the disease. Identification of intermediate phenotypes, such as particular biological markers or responses to functional tests, should be useful to identify subgroups of patients and to give hints for finding new genes responsible for PHA1. More generally, discovery of new hMR mutations in PHA1 may allow the detection or better definition of recently discovered novel pathways of signal transduction and cross-talk; this presents exciting prospects for new therapeutic approaches toward modulating salt sensitivity and blood pressure.
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Acknowledgments |
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Footnotes |
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Received December 9, 2002.
Accepted February 5, 2003.
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and ß messenger ribonucleic acid isoforms of the human mineralocorticoid receptor in normal and pathological states. J Clin Endocrinol Metab 82:1345–1352This article has been cited by other articles:
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