(Hypertension. 1999;34:435-441.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Genetic, Biochemical, and Clinical Studies of Patients With A328V or R213C Mutations in 11ßHSD2 Causing Apparent Mineralocorticoid Excess
From Biologie Hormonale (G.M., J.F.), Hôpital Saint-Louis, France; Néphrologie, CHG (J.-M.M.), Annonay, France; Chimie Organique, Faculté de Pharmacie (A.B., H.G.), Paris, France; Service d'Explorations Fonctionnelles (M.G.), Hôpital Trousseau, Paris, France; Inserm U36 (P.C.), Collège de France, Paris, France; Fondation Jean Dausset CEPH (L.P.), Paris, France; and Biochimie, Faculté de Pharmacie (J.F.), Paris, France.
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Abstract |
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Abstract—Apparent mineralocorticoid excess is a recessively inherited hypertensive syndrome caused by mutations in the 11ß-hydroxysteroid dehydrogenase type 2 gene, which encodes the enzyme normally responsible for converting cortisol to inactive cortisone. Failure to convert cortisol to cortisone in mineralocorticoid-sensitive tissues permits cortisol to bind to and activate mineralocorticoid receptors, causing hypervolemic hypertension. Typically, these patients have increased ratios of cortisol to cortisone and of 5
- to 5ß-cortisol
metabolites in serum and urine. We have studied 3 patients in 2
families with severe, apparent mineralocorticoid excess and other
family members in terms of their genetic, biochemical, and clinical
parameters, as well as normal controls. Two brothers were
homozygous for an A328V mutation and the third patient was homozygous
for an R213C mutation in the 11ß-hydroxysteroid dehydrogenase type 2
gene; both mutations caused a marked reduction in the activity of the
encoded enzymes in transfection assays. The steroid profiles of the 7
heterozygotes and 2 other family members studied were completely
normal. The results of a novel assay used to distinguish 5- and
5ß-tetrahydrometabolites suggest that 5ß-reductase activity is
reduced or inhibited in apparent mineralocorticoid excess. In 1 patient
undergoing renal dialysis for chronic renal insufficiency, direct
control of salt and water balance completely corrected the
hypertension, emphasizing the importance of mineralocorticoid action in
this syndrome.
Key Words: hydroxysteroid • tetrahydrocortisone • hemodialysis • mutation • hypertension, genetic
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Introduction |
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Apparent mineralocorticoid excess (AME) is a rare and severe form of hypertension characterized by an early age of onset and signs of excess mineralocorticoid activity.1 2 It has an autosomal recessive mode of inheritance3 and is caused by mutations in the 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) gene, which result in a deficiency in the activity of the encoded 11ßHSD2 enzyme4 5 that catalyzes the conversion of cortisol to cortisone and of corticosterone to 11-dehydrocorticosterone.6 Cortisol and corticosterone are agonists with high affinity for the mineralocorticoid receptor, comparable to the principal mineralocorticoid hormone aldosterone, whereas cortisone and 11-dehydrocorticosterone have a low affinity for the receptor.7 The catalytic action of 11ßHSD2 ensures, in part, that binding and activation of the mineralocorticoid receptor is effected only by aldosterone, since this steroid is not a substrate for the 11ßHSD2 enzyme.
In patients with a hereditary defect of 11ßHSD2 enzymatic activity,
cortisol, which circulates at much greater concentrations than
aldosterone, acts as a potent mineralocorticoid hormone,
inducing hypervolemic hypertension. The AME syndrome has been
biochemically characterized by increased cortisol-to-cortisone ratios
in serum and urine, or of the urinary cortisol metabolites,
5ß-tetrahydrocortisol (5ßTHF) and 5-tetrahydrocortisol
(5THF), relative to the cortisone metabolite
5ß-tetrahydrocortisone (5ßTHE) (Figure 1). An increase in the ratio of urinary
5THF to 5ßTHF is also typically found in most of these
patients,2 8 9 for which no explanation has yet been
furnished.10 A second form of AME (AME type 2) has also
been reported,11 12 and its molecular basis has recently
been ascribed to mutations that partially inactivate the
11ßHSD2 enzyme.10 Here we report genetic, biochemical,
and clinical follow-up studies of 3 AME type 1 patients (2 of them
siblings), as well as their relatives, and 91 normal individuals. The
AME patients were investigated by a newly developed assay for
determination of the urinary 5-tetrahydroderivative of cortisone
(5THE) and dehydrocorticosterone
(5THA). Quantification of these steroids has enabled us to postulate
a mechanism for the increased 5THF-to-5ßTHF ratio encountered in
AME. One of our patients was subjected to long-term hemodialysis, and
she was evaluated both before and after dialysis.
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Methods |
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Patients A and B
Patients A and B are brothers of Portuguese origin whose parents are first cousins. They were diagnosed as having AME in 1993 on the basis of hypertension, hypokalemia, hypoaldosteronemia, hyporeninemia, and low excretion of urinary 5ßTHE compared with 5ßTHF and 5
THF.13 The 2 brothers have been repeatedly
evaluated for their urinary corticoid excretion and blood cortisol,
cortisone, renin, aldosterone, deoxycorticosterone,
and corticosterone levels. Similar studies were performed on their
mother, father, unaffected brother, and uncle.
Patient C
The third patient (C) was diagnosed at age 4 as having
arterial hypertension (140/60 mm Hg), hypokalemic
alkalosis, low plasma renin and aldosterone levels,
microcalcifications, and pseudocystic right kidney with fibrosis of 7
of 22 glomeruli on renal biopsy.14 A positive diagnosis of
AME was established at age 30, and the patient was reevaluated at the
beginning of 1997, before and after institution of
dexamethasone (DXM, 0.5 mg/d) therapy, and later in 1997
after hemodialysis (4 hours, 3 times a week) had been initiated. She
was subjected to the same biochemical and genetic
testing15 as patients A and B, together with her mother,
sister, and 3 children.
Control Subjects
Healthy, white, nonsmoking volunteers (51 women and 40 men),
with ages ranging from 21 to 46 years and taking no medication,
contraceptives, or licorice, provided blood samples at 8 AM
and 24-hour urine samples to establish the reference values of the
parameters tested. All investigations conformed to the
ethical standards of the Helsinki declaration (1975) as revised at
Tokyo (1983).
Analysis of Genomic DNA
Genomic DNA was extracted from peripheral blood
leukocytes, and the exons and intron-exon junctions of the 11ßHSD2
gene were amplified by polymerase chain reaction (PCR). The samples
were denatured at 94°C for 1 minute, followed by 30 amplification
cycles (94°C for 1 minute, 60°C to 70°C for 1 minute, and 72°C
for 2 minutes, with an additional 5 seconds in each cycle) and 1 cycle
at 72°C for 7 minutes. Amplified DNA fragments were purified from
low-melting-point agarose gels with Gelase (Epicentre Technologies),
and the purified DNA was then sequenced on both strands by the Sanger
method of dideoxynucleotide chain termination by using T7
Sequenase version 2 (Amersham).
In Vitro Mutagenesis
Mutations were introduced into the wild-type 11ßHSD2 cDNA by
site-directed PCR mutagenesis, as previously described.16
The PCR reaction was optimized to facilitate amplification of the
GC-rich (62%) sequence by using a mix of Taq DNA polymerase
(5 U/mL) and Pfu DNA polymerase (2.5 U/mL) in 200
mmol/L Tris, pH 8.8; 3 mmol/L MgCl2;
160 mmol/L NH4SO4; and
7.5% dimethyl sulfoxide in a single reaction.17 The
mutated 11ßHSD2 cDNAs were subcloned into the HindIII and
XbaI restriction sites of the pcDNA1 expression vector (In
Vitrogen).
Transfection and Expression Studies
Normal and mutated 11ßHSD2 cDNAs (2 µg) were transfected
into 70% confluent cells from a Chinese hamster ovary line (CHOP
cells, kindly provided by Dr James Dennis) with Lipofectamine (GIBCO
BRL) according to the manufacturer's instructions. CHOP cells were
grown in Ham's F12 medium with 2 mmol/L glutamine and 10%
decomplemented fetal bovine serum (Boehringer Mannheim). After
12 hours, the transfected cells were incubated with 2 nmol/L tritiated
and 200 nmol/L unlabeled steroid (cortisol or corticosterone), and the
resulting products were analyzed by
high-performance liquid chromatography with an
online ß-detection system (Radiomatic, Flo-one, Packard Instruments).
Apparent kinetic constants (Km and
Vmax) were calculated from 2-hour incubations of
2 nmol/L tritiated steroid with 10, 50, 200, 600, 1500, and 5000 nmol/L
unlabeled steroid and analysis by Lineweaver-Burk plot.
The results presented are the mean of 2 independent
experiments. The efficiency of the transfection was verified by
Northern blot analysis (5 µg total RNA) and reverse
transcription PCR (data not shown).
Biochemical Assays
Serum was drawn between 8 and 9 AM after 1 hour of
upright posture. Renin and aldosterone were evaluated by
radioimmunoassay with Renin III (ERIA Diagnostics Pasteur)
and TKAL (DPC) kits. Cortisol and cortisone in blood and 24-hour urine
were determined by radioimmunoassay after
chromatography as previously
described.18
Estimation of 17 hydroxycorticosteroids was carried out
by gas chromatography with flame-ionization detection
of the methyloxime trimethylsilyl ether derivatives after extraction,
hydrolysis, and purification of 24-hour urinary steroids as previously
described.13 To quantify 5THE and 5THA, which
coelute with 5ßTHF and 5THB, respectively, on OV1 columns, the
gaseous phase was separated into 2 parts and passed
simultaneously over an OV1 and an SPB20 capillary column
before detection of the steroids; the SPB20 column allows separation
and quantification of 5THE and 5THA. The remaining steroids were
determined from the OV1 effluent, directly for 5ßTHE, 5THF,
5ßTHB, and 5ßTHA and after subtraction of 5THE and 5THA for
5ßTHF and 5THB, respectively.
Gas Chromatography–Mass Spectrometry
The identity of the trimethylsilyl ether derivatives of the
steroids was assessed by mass fragmentography by using a Nermag R30-10
triple-quadrupole spectrometer and electron-impact ionization.
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Results |
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Gas Chromatography–Mass Spectrometry Analysis
Effective separation of 5
THE from 5ßTHF and of 5THA from
5THB was obtained on the SPB20 column (Figure 2). Identification of 5THE and 5THA
methyloxime trimethylsilyl ether derivatives by electron-impact
ionization mass spectrometry produced mass spectra that were identical
to those of 5ßTHE and 5ßTHA (Figure 2). The detection limit
of the method (zero+3SD) is 0.01 mg, with an interassay reproducibility
(coefficient of variation for 10 repeats) between 11% and 14%
for 5ßTHE, 5ßTHF, 5THF, and 5ßTHB and of 12% to 17% for
5THE, 5THB, 5THA, and 5ßTHA. Our normal values (see
Table) are in good agreement with those
of other authors,19 20 but the normal ratios we observed
are slightly wider than those usually reported.3 12 21
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Genetic Results
Direct DNA sequencing of 11ßHSD2 exons from patients A and B
revealed a homozygous mutation of codon 328 (exon 5) of the 11ßHSD2
gene, from GCG to GTG (A328V). The father and mother were heterozygous
for the same mutation, whereas the brother and uncle were homozygous
for the normal sequence.
Patient C had a homozygous mutation in codon 213 (exon 3) of CGC to TGC (R213C). Her mother, sister, son, and 2 daughters were heterozygous for the same mutation. Expression of the mutated cDNA, followed by 16 hours of incubation with tritiated steroid precursors (Figure 3), showed that the 2 mutant enzymes converted <5% of cortisol or corticosterone to cortisone or 11-dehydrocorticosterone, respectively. The normal 11ßHSD2 cDNA resulted in 100% conversion of the substrates under the same conditions. Both reverse transcription PCR and Northern blot analysis of RNA from the transfected cells verified the efficiency of the transfection and transcription of the mRNAs (not shown). The apparent Km and Vmax for the normal 11ßHSD2 enzyme in our system were, respectively, 117 nmol/L and 1.07 pmol · min-1 · well-1 for corticosterone and 254 nmol/L and 0.46 pmol · min-1 · well-1 for cortisol, consistent with reports from other authors using the same system.22 23 Similar constants could not be calculated for the mutant enzymes owing to their very low activity.
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Biological Results
None of the unaffected members of the 2 families explored,
including the heterozygous individuals and the homozygous normal
individuals, showed any metabolic abnormality in blood or
urine (kalemia, renin, aldosterone, cortisol, cortisone, or
their metabolites), as is expected for a recessively inherited
disease.
The 3 patients, on the contrary, displayed all of the features of AME
(the Table). Serum and urinary cortisone levels were low and
cortisol-to-cortisone ratios (F-to-E) were high. Owing to the reduced
conversion of cortisol to cortisone, urinary free cortisol was high in
non–DXM-treated patients. A disturbed balance between cortisol and
cortisone metabolites was observed in urinary samples, with an elevated
ratio of (5ßTHF+5THF) to 5ßTHE, due principally to diminished
secretion of 5ßTHE. This was accompanied by an increase in the
5THF-to-5ßTHF ratios and also the 5THE-to-5ßTHE ratios,
indicating a shift from 5ß-reductase toward 5-reductase
metabolism. The serum and urinary F-to-E and
(5ßTHF+5THF)-to-5ßTHE ratios remained elevated for patient A,
irrespective of the efficacy of blood pressure control, whereas
5THF/5ßTHF decreased to normal values after DXM treatment. His
cortisol clearance (as reflected by the
[5ßTHF+5THF+5ßTHE]-to–urinary free cortisol ratio) was
generally diminished, but the A-ring reduction constant
([5ßTHF+5THF]/urinary free cortisol) was normal.
In the urine of normal subjects, 5THE values were low compared with
5ßTHF, 5THF, and 5ßTHE values, indicating that cortisone is a
less-efficient substrate for 5-reductase than is cortisol, whereas
cortisol and cortisone have similar affinities for the 5ß-reductase
enzyme.
Clinical Results
In addition to the severe hypertension seen in patients A and B,
their uncle exhibited sustained hypertension (160 to 180/120 to
140 mm Hg), whereas their father, mother, and brother were
normotensive. When reevaluated in 1997, patient A was treated with
nifedipine LD 20 mg/d (a calcium
antagonist) and DXM 0.5 mg/d. Arterial blood
pressure remained elevated (172/106 supine). Plasma potassium was low
to normal (3.7 to 4.2 mmol/L), and urinary free cortisol was low,
reflecting the DXM treatment. Ultrasonography revealed slight, diffuse,
renal cortical atrophy, and the heart showed an eccentric left
ventricular hypertrophy, with a high cardiac
mass at 131 g/m2 (normal<125). Addition
of an angiotensin converting enzyme inhibitor
(benazepril 10 mg/d) to his therapy lowered blood pressure to 144/86
and the left cardiac hypertrophy regressed (cardiac mass
102 g/m2). However, within an additional 6
months, his blood pressure had again risen to 162/80. Additional
treatment with furosemide (40 mg/d) and amiloride (5 mg/d) resulted in
sustained lowering of blood pressure (140/90).
In 1997, patient B had followed no therapy other than potassium supplementation (24 mEq/d). Arterial blood pressure was 162/88 mm Hg supine. There was no sign of left ventricular hypertrophy. Renal ultrasonography was normal, but there was slight proteinuria (0.55 g/24 h) accompanied by high calcium and sodium excretion (9 mmol and 181 mmol/24 h, respectively). In spite of the potassium supplementation, serum potassium was low (3.1 to 3.3 mmol/L), as were renin and aldosterone, and free urinary cortisol was high (198 µg/24 h). A low-sodium diet and DXM 0.5 mg/d were recommended to the patient, which normalized blood pressure (145/85, 18 months later).
The mother of patient C had experienced 3 miscarriages before giving birth to 2 daughters and was diagnosed as having hypertension during her first pregnancy. The patient's grandmother was also hypertensive, whereas her sister and her 3 children were normotensive. Her father had a history of hypertension and had died of a cerebrovascular accident.
Patient C had been prescribed several classes of antihypertensive
agents over the last 20 years, including amlodipine (5 mgx2/d),
rilmenidine (1 mg/d), and urapidil (60 mgx2/d), with poor blood
pressure stabilization 
160/100 mm Hg. She also received 32 meq
K+/d to correct hypokalemia and calcium carbonate
(3.62 g Ca2+/d) and alfacalcidol (1 µg/d) to
correct hypocalcemia, which nonetheless remained at 1.75 mmol/L
(normal 2.4 to 2.62). She had previously undergone subtotal
parathyroidectomy for hyperparathyroidism that was secondary to the
persistent hypocalcemia but that had attained a degree of autonomous
regulation. Because analysis of her urinary corticoid
metabolites (the Table) was consistent with AME, her
antihypertensive treatment was modified by the addition of DXM (0.5,
then 1 mg/d), resulting in better control of blood pressure, and the
associated therapy was reduced to atenolol (50 mg/d) and DXM (1
mg/d). An attempt to withdraw the atenolol completely was followed by a
mild increase in blood pressure. At the beginning of 1997, she
presented with severe renal insufficiency and was put on
hemodialysis (4 hours, 3 times a week), enabling direct control of
water and salt balance that, with accompanying weight loss, further
improved her blood pressure. All antihypertensive therapy was then
progressively removed until her blood pressure was equilibrated by
dialysis alone.
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Discussion |
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Our results highlight the severe complications that may arise in inadequately treated AME patients and the clinical differences that can be observed in individuals with identical mutations. The A328V mutation has been independently reported in a 7-year-old Brazilian girl with AME24 whose heterozygous father was found to be hypertensive, with suppressed plasma renin activity and aldosterone and a persistently elevated (5
THF+5ßTHF)/5ßTHE ratio of 2.79 (normal 0.8 to 1.4), but with
normokalemia. This was the first such suggestion of hypertension with
an AME pattern of steroid metabolites in a heterozygote for an
11ßHSD2 mutation. In the family with an A328V mutation that we studied, there was little evidence for an effect of the mutation in heterozygous individuals. The heterozygous mother and brother were normotensive, and the uncle, who was homozygous for the normal sequence, had established hypertension. Furthermore, the biological exploration and steroid metabolites were completely normal for all heterozygotes in this family as well as in the other family investigated.
The 2 affected brothers displayed some clinical differences in the expression of the disease. Although untreated, patient B showed no sign of left ventricular hypertrophy, while his brother (patient A), who was receiving DXM therapy, had significant left ventricular hypertrophy. Clearly, there is variability of the clinical and biological phenotype independent of the 11ßHSD2 genotype.
The R213C mutation has been reported in 2 homozygous sisters with AME5 and in an unrelated male.25 We found the activity of the mutated enzyme to be <5% of the wild-type enzyme for both cortisol and corticosterone, which compares well with the 3.6% and 2.2%, respectively, previously reported.23
The most significant diagnostic feature for AME appears to
be the decrease of cortisone in blood and urine and the increased ratio
of 11-hydroxymetabolites to 11-oxometabolites of cortisol. The
(5ßTHF+5THF)-to-5ßTHE ratio and the cortisol-metabolizing
quotient (5ßTHF+ 5THF+5ßTHE/urinary free cortisol) were also a
useful diagnostic feature. The A-ring reduction constant
([5ßTHF+ 5THF]/urinary free cortisol) was always the same in our
patients as in normal subjects and thus seems to be a less useful
diagnostic indicator of AME.
The method of steroid determination used in this study allowed separate
quantification of 5THE. The amounts of 5THE secreted are low
compared with 5ßTHF, 5THF, and 5ßTHE, consistent with a
previous report26 that found <2% metabolism
of [4-14C]cortisol into 5THE and with the
values reported27 in cases of congenital adrenal
hyperplasia. Separate quantification of this metabolite confirms that
cortisone has a low affinity for the 5-reductase enzyme, whereas
cortisol has an approximately equal affinity for the 5- and
5ß-reductase enzymes. In normal subjects, both 5-reductase and
5ß-reductase metabolize cortisol, leading to approximately equal
amounts of 5THF and 5ßTHF, whereas cortisone is reduced mainly to
5ßTHE by 5ß-reductase. It appears that in AME patients,
5ß-reductase activity is reduced, as reflected by the generally low
ratios of 5ßTHF/F and 5ßTHE/E (the Table). In contrast, the
ratios of 5THF/F are in the normal range. These results suggest that
the increased ratio of 5THF/5ßTHF, often observed in AME patients,
is principally due to downregulation of 5ß-reductase activity of
undetermined origin. Although frequent in AME, the high
5THF-to-5ßTHF ratio is not universal.3 28 For
example, this ratio decreased in our patient A after DXM treatment for
reasons that are not clear at the present time. Further study of
steroid metabolism in AME patients by the methods
presented here is clearly warranted.
As expected in a patient with hypermineralocorticism, the blood pressure of our AME patient with chronic renal insufficiency was completely normalized by hemodialysis, enabling discontinuation of her antihypertensive therapy. This can be attributed to a lowering of serum sodium levels and direct control of water balance. In most AME cases reported, a low-sodium diet has had a beneficial effect on the control of hypertension. This suggests that studies of 11ßHSD2 function in hypertension should be centered on salt-sensitive and low-renin forms of hypertension.
Several studies in addition to ours have noted the occurrence of multiple miscarriages in mothers of AME patients.24 29 Because 11ßHSD2 is strongly expressed in the placenta and may play a protective role for the developing fetus,30 a more systematic study of this phenomenon may be warranted.
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Acknowledgments |
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This work was supported in part by a grant from the IPSEN Foundation for Therapeutic Research to L.P. We thank Dr Zygmund Krozowski for his generous gift of 11ßHSD cDNA; Drs Pierre-François Plouin, Christine Massien-Simon, and Marie-Christine Jubert for monitoring patients; Denis Lesage and Jean-Claude Tabet for mass spectrometry expertise; Florent Soubrier and Hany Soliman for helpful advice; and Marlyn Cohen, Françoise Quilin, Carole Ouabdelkader, Eliane Rolle, Laurence Homyrda, and François Rocher for expert technical assistance.
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Footnotes |
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Reprint requests to Dr Gilles Morineau, Biologie Hormonale, Hôpital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France.
Received March 8, 1999; first decision March 25, 1999; accepted May 24, 1999.
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