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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2024-2027
Copyright © 2004 by The Endocrine Society

CLINICAL CASE SEMINAR

In Vitro Expression Studies of a Novel Mutation {Delta}299 in a Patient Affected with Apparent Mineralocorticoid Excess

Karen Lin-Su, Ping Zhou, Nimmi Arora, Brian P. Betensky, Maria I. New and Robert C. Wilson

Department of Pediatrics, New York Presbyterian Hospital-Weill Medical College of Cornell University (K.L.-S., N.A., B.P.B., M.I.N., R.C.W.), and Department of Pediatrics, New York University School of Medicine (P.Z.), New York, New York 10021

Address all correspondence and requests for reprints to: Maria I. New, M.D., Department of Pediatric Endocrinology, New York Presbyterian Hospital, Weill Medical College of Cornell University, Room M-630, Box 103, 525 East 68th Street, New York, New York 10021. E-mail: minew{at}med.cornell.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive disorder that results in low renin hypertension and other characteristic clinical features. Typical patients present with severe hypertension, hypokalemia, and undetectable aldosterone. Most patients also have low birth weight, failure to thrive, and nephrocalcinosis. The 11ßhydroxysteroid dehydrogenase type 2 (11ßHSD2) defect is documented by demonstrating a failure to convert cortisol to cortisone. Here, we report a patient with typical phenotypic features of AME who does not carry any of the previously described mutations in the HSD11B2 gene. This female patient from a consanguineous Pakistani family presented at age 9 yr. She had a low birth weight compared with her siblings and presented with hypertension (225/120 mm Hg), low plasma renin activity, hypokalemic metabolic alkalosis, suppressed aldosterone, and bilateral nephrocalcinosis. Echocardiogram did not reveal left ventricular hypertrophy, and baseline ophthalmological evaluation did not demonstrate hypertensive retinopathy. However, at age 12 yr, she developed mild to moderate hypertensive retinopathy. Biochemical analysis showed an elevated urinary cortisol to cortisone metabolites ratio (tetrahydrocortisol and 5{alpha}-tetrahydrocortisol/tetrahydrocortisone) of 28 (normal, 0.66–2.44). She had a cortisol secretion rate of 0.43 mg/d (normal, 5–25 mg/d). Sequence analysis of the HSD11B2 gene revealed a novel homozygous {Delta}299 mutation in exon 5. In vitro expression in Chinese hamster ovary cells revealed that this mutation resulted in no activity.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
APPARENT MINERALOCORTICOID EXCESS (AME) is a form of severe low renin hypertension first described biochemically in 1977 (1). AME is an autosomal recessive disorder with prominent clinical signs and symptoms, including low birth weight, polyuria, failure to thrive, severe hypertension, hypokalemia, hypoaldosteronemia, suppressed plasma renin activity (PRA), and low secretion rates of corticosteroids. It has also been associated with nephrocalcinosis and sudden fatality in some cases. The features of AME are due to excess activation of the mineralocorticoid receptor (MR) by cortisol due to a defect in the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) (2, 3, 4, 5).

Although aldosterone is a more potent mineralocorticoid than cortisol, the MR binds both hormones with equal affinity (6). In mineralocorticoid target tissues (kidney and parotid), the MR is selective for aldosterone because of the presence of the type 2 isoform of 11ßHSD, which functions unidirectionally to convert cortisol to cortisone. Because cortisone does not bind to the MR, normal subjects are protected from cortisol intoxication by the action of this enzyme (2, 3). Aldosterone is not metabolized by the 11ßHSD2 enzyme and thus has unimpeded access to the MR. As cortisol is secreted in much higher concentrations than aldosterone, cortisol saturates the MR in patients with deficient 11ßHSD2 enzyme activity. The resulting inappropriate binding of cortisol to the MR causes sodium retention, volume expansion, and potassium excretion while suppressing PRA and aldosterone secretion. The clinical picture of mineralocorticoid excess due to cortisol binding in the absence of aldosterone is the hallmark of AME.

To date, two isoforms of 11ß-HSD have been identified and characterized. The type 1 isoform is NADP dependent and is expressed in several human tissues (7). Several lines of evidence indicate that the enzyme has primarily reductase activity (8, 9). The type 2 isoform is NAD dependent and has only dehydrogenase activity (10, 11). It localizes along with the MR in the distal nephron (10, 12, 13, 14, 15).

The human cDNA was cloned and sequenced (11). The gene for 11ßHSD2 (HSD11B2) has been cloned and localized to chromosome 16q22 (16, 17). More than 20 specific mutations in the HSD11B2 gene have been reported to date (18, 19, 20, 21, 22, 23, 24, 25, 26).

Before the description of AME, it was believed that receptors determined the specificity of hormone action. However, patients with AME have demonstrated that receptors can be promiscuous with respect to ligands, and in fact, the specificity of the mineralocorticoid receptor depends on the enzyme activity of 11ßHSD2. We report here a case of low-renin hypertension in which a new gene mutation produces a deficiency in the enzyme 11ßHSD2.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical studies

This patient was studied under an institutionally approved protocol of the Children’s Clinical Research Center of Weill Medical College of Cornell University. Informed written consent was obtained before the study. Blood pressure was measured every 2 h throughout hospitalization with a mercury sphygmomanometer after the patient had been supine for 10 min or more. The given diet was calculated for calories, sodium, and potassium by the Children’s Clinical Research Center kitchen. Twenty-four-hour urine collections were measured for urinary steroids, sodium, potassium, calcium, and creatinine. Blood samples for steroids, PRA, and electrolytes were collected daily at 0800 h.

Hormonal studies

Hormone studies were performed after all antihypertensive medications had been discontinued for 10 d. Serum cortisol, aldosterone, deoxycortisone, corticosterone, testosterone, dehydroepiandrosterone, {Delta}4-androstenedione, and estradiol were measured according to previously reported methods (27, 28, 29, 30, 31). PRA was measured by the method described by Sealey et al. (32). Urinary steroid metabolites were measured by assays, as described by Shackleton et al. (33).

Metabolic studies

Cortisol secretion rate and cortisol half-life were determined as previously described (1, 5, 34, 35).

Molecular analysis

In this patient, exons 2–5 of the HSD11B2 gene were sequenced as previously described (5). Exon 1 was PCR-amplified with primers 1s and 4a as previously described (21) using the FailSafe PCR PreMix Selection Kit (Epicenter Technologies, Madison, WI) under the following conditions: 200–300 ng of previously denatured DNA for 5 min at 95 C. DNA, 25 µl PreMix H, 100 ng of each primer, and 0.5 µl (2.5 U) FailSafe PCR Enzyme Mix in 50 µl. The samples were amplified on an PerkinElmer 2400 DNA Thermal Cycler (PerkinElmer, PE Applied Biosystems, Foster City, CA) at 94 C for 10 min, followed by 30 cycles of 94 C for 30 sec, 60 C for 30 sec, and 72 C for 1 min, followed by one cycle at 72 C for 7 min. Fifty to 100 ng purified PCR product were used for sequencing at the Cornell BioResource Center DNA sequencing facility with approximately 8 pmol of either primer 1s or 4a.

In vitro expression studies

The human HSD11B2 cDNA was cloned into the expression plasmid pCI (Promega Corp., Madison, WI). Once the mutation was identified and a mutant oligonucleotide was synthesized, site-directed in vitro mutagenesis was performed using the GeneEditor kit from Promega Corp. We performed in vitro expression studies in Chinese hamster ovary (CHO) cells. These cells were plated in F-K12 medium containing 10% fetal bovine serum at 2 x 105 cells/well in 12-well plates the day before transfection. The following day, transfections were performed with vector alone, pCI, normal pHSD2, or the mutant plasmid, p{Delta}299, using the TransFast transfection kit following the procedure described by Promega Corp. Forty-eight hours after transfection, the medium was removed from the cells and replaced with medium containing [3H]cortisol (2 µM). After 4-h incubation at 37 C, the steroids were extracted with 3 vol methylene chloride, followed by separation by thin layer chromatography developing in 85% chloroform/15% methanol. The steroid spots were visualized by UV light and scraped for scintillation counting. Cortisol is a precursor for the 11ßHSD2 enzyme and was converted to cortisone. The percentage conversion to cortisone (E) from cortisol (F) was calculated by: cpm of E ÷ cpm of E + cpm of F x 100%.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical evaluation

The patient is an 11-yr-old Pakistani female from a consanguineous family (Fig. 1Go) who was found on routine physical examination to have severe hypertension of 225/120 mm Hg. Initial evaluation at a local hospital revealed suppressed PRA, undetectable aldosterone, and hypokalemic metabolic alkalosis. She denied headaches, vision disturbances, abdominal pain, polyuria, weakness, and licorice ingestion. She was born at 36 wk gestation via cesarean section secondary to fetal bradycardia with a birth weight of only 2.0 kg, in contrast with her siblings who had birth weights ranging from 3.6–3.9 kg. The postnatal course was uneventful. Her growth pattern was normal, and there were no developmental delays. Family history was significant for consanguinity (her mother’s great-grandfather and her father’s grandfather were brothers; Fig. 1Go). Family members with hypertension included her mother, maternal grandmother, and maternal uncle. The patient’s father did not have hypertension by history, but was unavailable for evaluation. Her general physical examination, including neurological examination, was unremarkable. Ophthalmological examination revealed mild to moderate hypertensive retinopathy.



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  		FIG. 1. Pedigree showing consanguinity (her mother’s great-grandfather and her father’s grandfather were brothers). Only the proband (arrow) and her parents were genotyped. Both parents were heterozygous for the {Delta}299 mutation, and the patient was homozygous for the {Delta}299 mutation.

 
Laboratory evaluation

The patient’s baseline biochemical profile revealed a suppressed PRA of 0.26 ng/ml·h (normal, 0.3–3.0), bicarbonate of 33 mmol/liter (normal, 22–32), potassium of 2.4 mmol/liter (normal, 3.2–5.2), and undetectable urinary pH 1 aldosterone (normal, 5–20 µg/d). Creatinine clearance and 24-h urinary protein were within the normal range.

An ACTH stimulation test using Cortrosyn revealed suppressed aldosterone with otherwise normal steroid response. The cortisol secretion rate was 0.43 mg/d (normal, 11.5 mg/d). Mass spectrometry of 24-h urinary steroid quantification showed an elevated tetrahydrocortisol (THF) and 5{alpha}THF/tetrahydrocortisone (THE) ratio of 28 (normal, 0.66–2.44; AME, 6.7–73.8).

Hypertension responded minimally to dietary salt restriction with a small decrease in blood pressure from 156/91 to 141/86 mm Hg and a slight increase in PRA from 0.34 to 0.96 ng/ml·h. There was no change in serum electrolytes after dietary salt restriction. After 3 months of treatment with spironolactone, a MR antagonist, at a dose of 300 mg/d, blood pressure improved to 129/77 mm Hg, and PRA increased to 2.30 ng/ml·h.

Imaging studies

A renal sonogram revealed medullary cystic changes bilaterally and increased echogenicity of the medullary pyramids suggesting nephrocalcinosis. There was no evidence of main renal artery stenosis. A magnetic resonance imaging of the head was normal. Echocardiogram showed dilation of the aortic root, whereas an electrocardiogram was normal.

Genomic analysis of the HSD11B2 gene

DNA sequencing of the patient’s HSD11B2 gene revealed homozygous deletions of codon Y229 (Fig. 2Go). Both parents were found to be heterozygous for this deletion (Fig. 2Go).



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  		FIG. 2. HSD11B2 gene DNA sequencing. A, Sequence from a normal patient, Y299. B, Sequence from the mother, heterozygous {Delta}299. The father’s sequence is the same as that of the mother’s (data not shown). C, Sequence from the patient, homozygous {Delta}299.

 
11ßHSD2 expression studies

To show that this mutation results in decreased expression of 11ßHSD2, we performed site-directed mutagenesis, followed by expression studies in CHO cells. Figure 3Go shows that the expression of {Delta}299 resulted in the conversion of [3H]cortisol to [3H]cortisone at the same levels as that of vector alone.



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  		FIG. 3. In vitro expression of {Delta}299. In vitro expression was performed in CHO cells twice in triplicate. Plasmid pHSD2 contains the normal HSD11B2 cDNA. Plasmid pCI is the vector only. Plasmid pD299 has codon Y299 deleted.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we describe a novel mutation in the HSD11B2 gene of a patient with AME. Our in vitro expression studies confirmed that the {Delta}299 mutation resulted in no enzymatic activity. As would be expected with homozygous mutations, this patient demonstrated a clear phenotype for AME. Consistent with typical features of AME, this patient presented with hypertension, hypokalemic alkalosis, hyporeninemia, and hypoaldosteronemia, all attributable to the defective metabolism of cortisol to cortisone. Additionally, the cortisol secretion rate measured in this patient was markedly diminished. Cortisol secretion rates are characteristically quite low in patients with AME, ranging from 0.05–0.83 mg/d compared with the normal secretion rate of 5–25 mg/d (5). The low cortisol secretion rate associated with AME is probably attributable to the prolonged half-life of cortisol resulting from its defective metabolism to cortisone (5). Other features associated with AME that were demonstrated in this patient include low birth weight, nephrocalcinosis, and some sequelae of hypertension (hypertensive retinopathy and dilated aortic root). Although not present in this case, other clinical features that may be seen in patients with AME include failure to thrive, developmental delay, left ventricular hypertrophy, renal insufficiency, central nervous system dysfunction, and even sudden fatality.

Because the principal problem in AME is overactivity of the MR due to excessive binding of cortisol, this disorder can be effectively treated with blockade of the receptor with spironolactone. As expected, this patient responded quite well to high dose spironolactone with normalization of her blood pressure, PRA, and potassium. The high dose of spironolactone required to achieve normalization is not uncommon among patients with AME and may be related to the severity of the disease (5). Others have successfully treated AME with dexamethasone, which acts by suppressing cortisol secretion (4).

The diagnosis of AME should be suspected in patients with features of low birth weight, failure to thrive, polyuria, polydipsia, and hypertension. If biochemical evaluation demonstrates hypokalemic alkalosis, hyporeninemia, and hypoaldosteronemia, possible diagnoses include AME, 11ß-hydroxylase deficiency, 17{alpha}-hydroxylase deficiency, deoxycorticosterone-producing tumor, or excess licorice ingestion. A 24-h urine collection for measurement of cortisol metabolites should be performed and analyzed for the ratio of THF plus 5{alpha}THF/THE, with an abnormally high ratio being suggestive of AME. The ideal biochemical diagnostic procedure for diagnosing AME is measurement of the conversion of cortisol to cortisone by measuring 3H2O release after infusing tritiated [11-3H]cortisol (normal conversion, 90–95%) (5). However, this procedure is technically difficult and not widely available. If the urine ratio of THF plus 5{alpha}THF/THE is suggestive of AME, DNA analysis can be used to confirm the diagnosis.

DNA analysis of the HSD11B2 gene is an important and effective means of confirming the diagnosis of AME. Identification of the new mutation described here as well as future new mutations will strengthen DNA analysis as an invaluable tool for genetic counseling in affected families.


   Footnotes
 
This work was supported by United States Public Health Service Grant HD-00072 and Children’s Clinical Research Center Grant RR-06020.

Abbreviations: AME, Apparent mineralocorticoid excess syndrome; CHO, Chinese hamster ovary; 11ßHSD2, 11ß-hydroxysteroid dehydrogenase type 2; MR, mineralocorticoid receptor; PRA, plasma renin activity; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

Received July 22, 2003.

Accepted February 18, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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