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Original Studies |
Laboratoire de Biochimie Endocrinienne (S.P.-D., Y.M.), INSERM U329, Université de Lyon et Hôpital Debrousse, 69322 Lyon Cedex 05; Clinique Endocrinologique (J.T.), Hôpital de l’Antiquaille, 69321 Lyon Cedex 05; Département de Pédiatrie (O.R.), Hôpital-Nord, 42055, Saint-Etienne; INSERM U36 (P.M., K.M.C., L.P.), Collège de France, 75005 Paris; Laboratoire d’étude des minéralocorticoïdes (B.A.-F.), CHU Pitié-Salpétrière, 75634 Paris, France
Address all correspondence and requests for reprints to: Professor Yves Morel, INSERM U329, Laboratoire de Biochimie endocrinienne et moléculaire, Hôpital Debrousse, 29, rue Soeur Bouvier, 69322 Lyon Cedex 05, France; E-mail: morel{at}lyon151.inserm.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Isolated deficiencies of aldosterone biosynthesis are caused by mutations in the CYP11B2 gene (2, 4, 5). These disorders are characterized clinically by salt wasting, hyponatremia, and hyperkalemia, often presenting as infants with failure to thrive. Plasma renin activity is elevated, plasma aldosterone is low or undetectable, and the plasma levels of the steroid precursors DOC and 18OHDOC are elevated. Two forms of aldosterone synthase deficiency can easily be distinguished (1, 6, 7). In the first type, corticosterone methyloxidase type I (CMO I) deficiency (6) or aldosterone synthase deficiency (ASD) type 1 (1, 7), aldosterone is undetectable in plasma, while its immediate precursor, 18OHB, is low or normal. The ratio of B to 18OHB is typically elevated in these patients (8). In the second form (CMO II deficiency or ASD type 2), aldosterone can be low or normal, but at the expense of increased secretion of its precursor, 18OHB. Consequently these patients have a greatly increased ratio of 18OHB to aldosterone and a low ratio of B to 18OHB (8). The classification and nomenclature of these deficiencies has been the subject of several reports in the literature (1, 7), and the reason for the biochemical differences is poorly understood. Our results show that clinical phenotypes do not necessarily fit within such a rigid classification. Clearly more studies are required to correlate the genetic mutations that are found (and the activities of the encoded mutant enzymes) with the observed clinical phenotypes.
We studied two affected twins who presented with severe salt wasting in the first month of life and who have undergone two biological investigations, one at birth (9) and one twenty years later, both of which suggest CMO-I deficiency or ASD type 1. Both patients also have a hypocalciuric hypercalcemia of unknown origin, which is assumed to be unrelated to the aldosterone synthesis defect (10). The molecular studies of the CYP11B2 gene show that they are homozygous for two deleterious mutations, E198D and V386A, and a polymorphism, R173K, frequently found in our French population. The in vitro transfection studies of these two mutants show an enzyme with a decreased 11ß-hydroxylase activity and an impaired 18-hydroxylase activity, more typically found in patients with the CMO II phenotype than the CMO I phenotype. This apparent discrepancy between the in vitro activity of the mutant enzyme and the clinically observed phenotype demonstrates that the genetic basis of the different forms is not yet completely understood and that further studies of the relationship between phenotype and genotype are necessary.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The two twin boys (twin 1 and twin 2) were delivered by Caesarean section and had healthy parents, without apparent consanguinity, although natives of the same region in France. The birth weights were normal (3.070 and 2.550 kg). In the first days of life, serum sodium levels were low, and they decreased to 116 mmol/L at day 8 (twin 1) and 109 mmol/L at day 12 (twin 2) without hypokalemia (4.2 and 4.6 mmol/L). On day 12, the weight loss was respectively 20% and 25%. Oral administration of NaCl (1 g/kg/day) cured the hyponatremia and induced a normal weight increase. Three months later, fludrocortisone (50 to 75 µg/day) was prescribed. The diagnosis of a probable 18-hydroxylase deficiency was made based on a decreased aldosterone secretion rate (16.5 and 27.6 µg/day vs. 60–150 µg/day in normal subjects), an increased plasma renin activity (2, 340, and 3, 740 ng/L/min vs. 90 ± 30 ng/L/min in normal subjects), and a decreased 18-OHB secretion rate (47 and 48 µg/day vs. 145–460 µg/day in normal subjects) (9). These studies were performed when the boys were 11 months old after stopping the fludrocortisone treatment for 2 weeks and under oral NaCl administration (3.75 to 4 g/day). At this time, plasma sodium concentrations were low (133 and 130 mmol/L), and they decreased markedly (to 121 and 108 mmol/L) after stopping salt supplementation, accompanied by loss of weight (300 g). Fludrocortisone treatment was then decreased to 25 µg/day. Compliance to the treatment was irregular, but subsequent growth, puberty, and mental development were normal. Nevertheless, a salt wasting crisis occurred twice in twin 1 (at 11 yr and again at 14 yr) after discontinuing the treatment. Serum calcium level measured repeatedly was slightly elevated (between 2.5 and 2.9 mmol/L), with daily urinary calcium excretion between 0.6 and 0.9 mmol.
When the twins were 20 yr old, biological investigations were again carried out (see below). The patients were clinically normal at the time: height, 172 and 172 cm; weight, 54 and 54 kg; plasma sodium, 140 and 140 mmol/L.
Informed consent for this study has been obtained from these two twins and their parents, according to our institutional guidelines.
Hormonal assay, ACTH test
Fludrocortisone treatment (75 µg/day) was stopped 8 days (twin 1) or 2 days (twin 2) before the test. The twins were supine for 2 h before blood samples were taken. Plasma steroid concentrations were measured before, 30 min after, and 60 min after intravenous injection of ACTH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) (0.25 mg). Plasma PTH and renin were measured by radioimmunoassay. Plasma DOC, 18-OHDOC, corticosterone, and 18-OHB were measured by radioimmunoassay after chromatographic separation (11), plasma cortisol by a competitive protein binding assay with 3H labeled cortisol using horse transcortin and plasma aldosterone by a competitive assay with 3H labeled aldosterone.
Selective PCR amplification of CYP11B2 gene fragments
Peripheral blood samples of the twins, both parents, and 25
unaffected and unrelated individuals were obtained, and genomic DNA was
prepared as previously described (12). Selective amplification of the
CYP11B2 gene was performed in 5 fragments by PCR, using the
oligonucleotides shown in Table 1
, in 100
µL reactions containing 750 ng genomic DNA, 50 M of each
primer, 200 µM of each dNTP, 2.5 U Taq
polymerase, and 1 x Taq reaction buffer (Eurobio, les
Ulis, Paris, France). Concentration of MgCl2 was optimized
for each amplified fragment (Table 1). The PCR program on a GeneAmp
9600 thermocycler (Perkin-Elmer, Norwalk, CT) was 95 C for
5 min, followed by 30 cycles of 15 sec at 95 C, 15 sec at 56 C (50 C
for exons 8–9), and 20 sec at 72 C, with a 72 C final extension for 10
min in the last cycle.
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PCR products were purified with microspin S400-HR columns (Pharmacia Biotech, Uppsala, Sweden) to remove salt, residual primers, and unincorporated deoxynucleotide triphosphates. Approximately 80–100 ng of PCR products were directly sequenced using the AmpliTaq FS dye terminators kit (Applied Biosystems, Foster City, CA). Each exon was sequenced on both strands. After 25 cycles in 9600 GeneAmp (Applied Biosystems) (30 sec at 95 C and 4 mn, 30 sec at 60 C), the reaction products were purified on sephadex G50 microspin columns, dried under vacuum, and dissolved in 4 µL of a (5:1) formamide/EDTA mix. The electrophoresis was performed with a 7% acrylamide/bis acrylamide 19/1 sequencing gel during 10 h with a 373A model automatic sequencer, and the data were analyzed using Sequed software (Applied Biosystem). Exons 3 and 7 were studied in the same way in 25 unaffected and unrelated persons.
Mutagenesis and transient transfection assays
The missense mutations were introduced into normal CYP11B2 complimentary DNA by PCR using oligonucleotides containing the desired change (13). Constructs were made containing each mutation, separately and in combination with the other mutations, as previously described (4). For each mutation, DNA from plasmid pCMV4-B2 (14) was amplified with Pyrococcus furiosis DNA polymerase (Stratagene, La Jolla, CA) in two overlapping segments, each using one oligonucleotide corresponding to either the 5' or 3' end of the CYP11B2 coding sequence, and one containing a desired mutant sequence. The 5' and 3' amplified segments were then gel purified, combined in a single reaction mixture, denatured, annealed, and extended to produced a full-length molecule containing the mutant sequence, which was then amplified using the primers from the 5' and 3' ends of the coding sequence. Restriction sites were included in these flanking primers to facilitate cloning into the expression vector pCMV4 (15). The complete sequence of each construct was then determined to ensure that no unwanted mutations had been introduced by PCR. Further mutations were then introduced as necessary by repeating the above procedure with the DNA containing the previous sequence changes and appropriate oligonucleotides. Human adrenodoxin and adrenodoxin reductase cDNAs were subcloned into the pCMV4 vector as described (4), from clones kindly supplied by Dr. W.L. Miller (16, 17). Individual CYP11B2 constructs (2.5 µg) were cotransfected along with pCMV4 constructs encoding human adrenodoxin and adrenodoxin reductase (0.5 µg each) into 105 COS-7 cells using 15 µL Lipofectamine (Gibco BRL, Paisley, Scotland) according to the manufacturer‘s instructions. The activities of the CYP11B enzymes expressed during the following 24- to 48-h time period were determined by including 0.825 µM 14C-labelled DOC in the medium and analyzing the steroids produced by thin layer chromatography as described (18). The amounts of aldosterone produced in parallel experiments performed with unlabelled DOC were determined by radioimmunoassay.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The hormonal profile of two twins diagnosed in the neonatal period
as having a defect of aldosterone biosynthesis were reevaluated at 20
years of age. A short ACTH test was performed 8 days and 2 days after
discontinuing their fludrocortisone treatment, in twin 1 and twin 2
respectively. Plasma steroid concentrations are listed in Table 2. Aldosterone and 18-OHB values were low
and were not stimulated by ACTH, in contrast to cortisol.
Corticosterone, DOC, and 18-OHDOC basal values were elevated in twin 1
and normal in twin 2. Comparison of hormonal data of the two twins
shows that the maximal values under ACTH were identical; the lower
basal values of twin 2 could be the consequence of the shorter period
between testing and discontinuation of the treatment. The
18-OHB/aldosterone ratio was low (7.2 and 7.25), the
corticosterone/18-OHB ratio was increased (80 and 78), and plasma renin
level was increased (72.1 and 15.8 pg/mL vs. 7.8 ± 1.2
in normal subjects). According to the usual nomenclature, this defect
should be termed CMO I deficiency or ASD type 1.
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Amplification and sequencing of DNA of the two affected twins and their parents
To confirm the diagnosis of aldosterone synthase defect type I in
these twins, the CYP11B2 gene of both young men was
specifically and entirely amplified from the DNA samples, and the nine
exons and the exon/intron boundaries were sequenced. Three apparent
missense mutations were identified in this gene, each of them
homozygous. Two mutations were located in exon 3; one of codon 173
where an arginine (AGG) was substituted by a lysine (AAG) (Fig. 1), and the other of codon 198 where a
glutamic acid (GAA) was substituted by an aspartic acid (GAC) (Fig. 1).
The third mutation has been previously described and was found in exon
7, being the substitution of a valine (GTG) for an alanine (GCG) at
codon 386 (Fig. 1). Both parents bore the three sequence changes on
only one of alleles. The fact that they were heterozygous for the
R173K, E198D, and V386A substitutions simultaneously suggests the
possibility of cryptic consanguinity or a founder effect in the
population (Fig. 1).
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Alignment of aldosterone synthase amino acids sequences in 5 species (human, mice, rat, hamster and bovine) showed that the glutamic acid in position 198 was highly conserved suggesting a functional role of this amino acid in enzymatic activity. A similar comparison of the 11ß-hydroxylase sequence in 7 species (human, mice, rat, guinea pig, pig, sheep, and bovine) gave the same result, with E198 in all sequences.
Enzymatic activity of the encoded aldosterone synthase mutants
In control transfections using CYP11B2 cDNA constructs
100% of the DOC substrate was converted to corticosterone, which was
in turn converted to 18OHB and aldosterone, demonstrating the expected
11ß-hydroxylase, 18-hydroxylase and 18-oxidase activities of the wild
type enzyme (Fig. 2). Control transfections with the
CYP11B1 sequence showed 100% conversion of DOC to B but
very little further activity and, in particular, no aldosterone was
produced. Transfections with the vector alone did not convert the
substrate. CYP11B2 cDNA constructs containing either of the
mutations V386A or E198D encoded enzymes able to catalyze the synthesis
of aldosterone, although with reduced efficiency. However when both
mutations were introduced into the same construct, the resulting
encoded enzyme displayed a slightly decreased 11ß-hydroxylase
activity, a large decrease of 18-hydroxylase activity and no detectable
18-oxidase activity. It was therefore unable to catalyze the final two
steps in the synthesis of aldosterone. This result is reminiscent of an
earlier study where both a R181W and the V386A mutations were required
in vivo to cause the aldosterone synthase deficiency (4). In
that study the transfection studies showed that the R181W mutation
alone was sufficient to abolish the 18-hydroxylase activity of the
encoded enzyme and the reason for the necessity of the apparently
benign V386A mutation was not evident. Our result differs from that
study in that each mutation alone has little effect on the activity of
the encoded enzyme, but there is nevertheless a significant interaction
between the mutations leading to the loss of C18 activity. This loss of
activity was also observed in constructs containing all three of the
amino acid changes R173K, E198D and V386A together, with a further
reduction in the efficiency of the 11ß-hydroxylase step.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Genetic studies of aldosterone deficiency have generally found mutations in the CYP11B2 gene (4, 5, 19, 20, 21, 22, 23). The first mutations were described in twelve patients with the type 2 deficiency in seven Jewish families of Iranian origin, all of whom were homozygous for two mutations, R181W and V386A (4, 5). Evidently both mutations are required to produce the disease because family members homozygous for only one were clinically and biologically normal. In vitro, an enzyme with the two substitutions, R181W and V386A, had normal 11ß-hydroxylase activity, severely reduced 18-hydroxylase activity and no 18-oxidase activity. In a later study, a patient with a typical clinical and hormonal profile of the type II deficiency was found to be a compound heterozygote for two genetic lesions, R181W-delC372 and T318M-V386A. The delC372 deletion, causes a shift in the reading frame of the gene product, and is expected to abolish all activities of the P450c11AS protein (21). The second allele was also found to be incapable of producing aldosterone in vitro, although the intermediate 11ß-hydroxylase activity was not studied. A T318M mutation was found in CYP11B1 in a patient with 11ß-hydroxylase deficiency and in vitro study showed this mutation totally abolished the enzyme activity (24). Thus it might be expected that the same mutation in CYP11B2 would impair its 11ß-hydroxylase activity. Nevertheless a CYP11B2 enzyme with the T318M substitution was found to catalyse conversion of DOC to corticosterone (Pascoe et al., personal communication).
Some patients with the type II deficiency have mutations of the CYP11B2 gene that do not modify aldosterone synthase activity or have no mutations in coding regions at all (25). If no mutation is found in the promoter or introns of these CYP11B2 genes, these results leave open the possibility that other enzymes, also involved in mineralocorticoid biosynthesis, may be defective in this disease.
Only four lesions of the CYP11B2 gene have been described in the type I deficiency, all abolishing completely the activity of the aldosterone synthase enzyme: a deletion of 5bp in exon 1 causing a frameshift and premature stop codon (23), two single point mutations in codons for highly conserved amino acids, R384P (20) and L461P (22), and a nonsense mutation, E255X (19).
With the exception of the patients noted above, where no mutation modifying enzymatic activity were found, the distinction between the two types of aldosterone deficiency seems to correlate with the activities of the encoded enzyme. All cases of the type I deficiency correspond to mutations which completely abrogate the activities of the encoded enzyme. Consequently aldosterone is undetectable and synthesis of the steroid precursors B, 18OHB and 18OHDOC could be catalyzed only by CYP11B1. The ratio B/18OHB is typically greater than 40.
In the type II deficiency the encoded enzyme could have some residual activity, notably a near normal 11ß-hydroxylase activity. Aldosterone levels are low and are achieved at the expense of greatly increased secretion of the immediate precursor 18OHB. Consequently the B/18OHB ratio is less than 10 and the 18OHB/aldosterone ratio greatly elevated. The residual enzymatic activity could also be responsible for conversion of some of the 18OHDOC (which is secreted in excess) into 18OHB, contributing to the hypersecretion of this steroid, which is typical of this form of the deficiency (26). The origin of the low amounts of aldosterone observed in these patients is not clear, but may also be due to a residual activity of the mutant enzyme. Alternatively a less efficient aldosterone synthesis pathway, utilizing for example the 18OHDOC which is hypersecreted, may be induced.
The present study of two twins with aldosterone synthase deficiency seems to be inconsistent with the previously observed correlation of phenotype and enzymatic activity. Clinically, the two twins presented a severe salt loss at birth and some recurrent crises of salt loss in infancy after discontinuing their treatment and induced by infection. Biologically, we observed low aldosterone and 18-OHB levels associated with a high B/18-OHB ratio, a pattern typical of CMO I deficiency. Nevertheless the presence of some measurable aldosterone indicates an intermediate form of the deficiency. The sequencing of the CYP11B2 gene confirmed the presence of mutations in the gene. Our two twins were homozygous for three sequence changes leading to amino acid substitutions: R173K and E198D in exon 3, and V386A in exon 7. The point mutation V386A has been already described in CMO-II patients in several studies (4, 21) and is also polymorphic in the normal French population (4% of chromosomes carrying this mutation). Evidently it has little effect on the activity of the encoded enzyme without the presence of additional sequence changes. R173K is also polymorphic and in fact a lysine at codon 173 is the more common allele (27). In our control population, Lys173 was found in 86% of alleles and only 14% had the arginine originally reported (28). The third sequence change in this family, E198D, is a novel point mutation. A glutamine in this position is highly conserved in all species of the both enzymes, CYP11B1 and CYP11B2. In sequencing studies of the CYP11B1 (120 chromosomes) and CYP11B2 genes (60 chromosomes), Glu198 was invariant.
Expression of cDNA constructs containing these sequence changes in COS-1 cells, showed that each of the substitutions alone induced at best a very small loss of enzymatic activity. However cDNAs with the mutations E198D in combination with either V386A or V386A plus R173K encoded enzymes with a reduced residual 11ß-hydroxylase activity, but no further catalytic activity. This pattern of activity of the mutant enzyme is intermediate between those observed previously for the type I and type II deficiencies, but is closer to those of the type II deficiency phenotype. In contrast the clinical phenotype is closer to a complete deficiency in aldosterone synthesis. A possible explanation for this disparity is that the 11ß-hydroxylase activity of the mutant CYP11B2 enzyme could be severely impaired in our patients compared to the wild type enzyme, but that this is not apparent in our transfection assay. A low efficiency of conversion of DOC to corticosterone, for example, may permit substantial conversion of the substrate during the 24 hr period of incubation in the transfection assay, but nevertheless be inadequate for efficient conversion in vivo. Further studies are clearly required to clarify the phenotype to genotype relationship in isolated aldosterone synthase deficiencies.
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Acknowledgments |
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Footnotes |
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2 S. D. is the recipient of a studentship from the
Ministère de la Recherche et de la Technologie.
3 Supported by a grant from the Fondation IPSEN for therapeutic
research and the Fondation pour la Recherche Médicale.
Current address: Fondation Jean Dausset CEPH, 75010 Paris,
France.
Received May 21, 1998.
Revised July 30, 1998.
Accepted July 31, 1998.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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q25 are expressed in steroidogenic tissues. Proc
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