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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2434-2437
Copyright © 1999 by The Endocrine Society

Original Studies

Polymorphisms of Amiloride-Sensitive Sodium Channel Subunits in Five Sporadic Cases of Pseudohypoaldosteronism: Do They Have Pathologic Potential?1

Keiko Arai, Keith Zachman, Tamotsu Shibasaki and George P. Chrousos

Department of Physiology, Nippon Medical School (K.A., T.S.), 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (K.Z., G.P.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Keiko Arai, M.D., Department of Physiology, Nippon Medical School, 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. E-mail: arai_keiko/phys2{at}nms.ac.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Mineralocorticoid receptor (MR) and postreceptor defects in the aldosterone-responsive amiloride-sensitive sodium channel (ENaC) subunits have been suggested as potential loci of the defect in this disease, whereas recently defects in MR and ENaC subunits were reported in familial PHA cases. Here we studied the ENaC subunit {alpha}, ß, and {gamma} complementary DNAs (cDNAs) in a series of five sporadic cases of PHA, whose MR cDNA contained nonconservative homozygous (C944->T944, Ala241->Val241) and/or a conservative heterozygous substitutions (A760->G760, Ileu180->Val180), which, however, were also present at high frequencies in a control population with apparently normal salt conservation. We found a nonconservative substitution (A2086->G2086, Thr663->Ala663) in the {alpha}ENaC in all five of our patients, two of whom were homozygous and three of whom were heterozygous for this alteration, which was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively. We also found a nonconservative homozygous substitution (C1006->G1006, Pro336->Ara336) in the ßENaC and three nonconservative and conservative homozygous substitutions (T554->A554, Trp178->Arg178; C1526->G1526, Pro501->Ala501; T1862->G1862, Ser614->Ala614) in the {gamma}ENaC of all five of our patients and in a substantial proportion of control subjects. Interestingly, when the patient group was compared to controls, a significantly increased concurrence of the MR and {alpha}ENaC polymorphisms was found in the patients (P < 0.025). We conclude that the changes identified in the cDNA of the three ENaC subunits in the patients with sporadic PHA are polymorphisms, which on their own have no apparent pathophysiological significance. We hypothesize, however, that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MR or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PSEUDOHYPOALDOSTERONISM (PHA), a congenital condition that presents in infancy with urinary salt wasting and failure to thrive, has been reported in more than 70 patients (1, 2). Approximately one fifth of these cases were familial (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). All patients had renal tubular unresponsiveness to aldosterone, whereas some had multiple mineralocorticoid target tissue involvement, including the sweat and salivary glands, and the colonic epithelium (8, 10, 13, 14). In the kindreds with PHA, both an autosomal dominant and a recessive form of genetic transmission were observed (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). The mineralocorticoid receptor (MR) was considered a potential candidate for this condition (15, 18, 19, 20). However, no molecular defects were found in the MR complementary DNA (cDNA) and/or the 5'-regulatory region or the first untranslated exon of its gene in 7 recently reported patients, including 5 of our cases, with the exception of a recent report of a family with autosomal dominant PHA (20, 23, 24, 25, 26, 27). In the latter kindred, affected members had 1 of their MR alleles knocked out, suggesting that full expression of the MR is necessary for salt conservation (20). These data suggested that a postreceptor defect in the aldosterone signal transduction, such as the amiloride-sensitive sodium channel (ENaC), might be involved in the pathophysiological mechanism of this syndrome in the majority of cases.

The rat and human ENaC consist of three subunits, {alpha}, ß, and {gamma}, whose cDNAs were recently cloned (28, 29, 30, 31). These three subunits form a channel located at the apical site of renal epithelial cells of the distal convoluted tubule that allows passive transport of sodium into the cell in response to aldosterone. Whereas most of sodium transport functions lie within the {alpha}-subunit, the ß- and {gamma}-subunits play synergistic roles and are required for full function (29, 31). Recently, several studies demonstrated abnormalities of the ß- and {gamma}-subunits in patients with Liddle’s syndrome, a rare condition whose pathophysiological mechanism is excessive reabsorption of sodium by the distal convoluted tubule, i.e. the mirror image of PHA (32, 33, 34). These reports suggested that the ENaC might be the postreceptor locus of the defect in many patients with PHA; accordingly, mutations of the{alpha}- and ß-subunits of the ENaC were reported in PHA patients from autosomal recessive kindreds (35, 36). In this study, we examined the cDNA structure of the three subunits of ENaC cDNAs in our five sporadic patients with PHA (23, 26).


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

We examined the cDNAs and genomic DNA of the 3 subunits of ENaC in 5 previously reported patients with PHA and 42 unrelated control subjects with apparently normal salt conservation (23, 26). We summarize the clinical, biochemical, and hormonal characteristics of the patients in Table 1Go.


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  		Table 1. Clinical and biochemical characteristics of sporadic patients with PHA

 
Case 1

The proband, a 17-yr-old white male, was born by spontaneous vaginal delivery at full term. In the first week of life, he developed severe dehydration, hyponatremia, hyperkalemia, and acidosis, associated with profound urinary salt loss. After a stormy course, he had an extensive evaluation at the Pediatric Clinical Research Unit of New York Hospital-Cornell Medical Center, which led to the diagnosis of pseudohypoaldosteronism and confirmed the presence of multiple organ resistance to aldosterone (8). He was maintained on high doses of salt and up to the age of 7 yr required frequent hospital admissions for iv hydration. On this first admission to the NIH at the age of 16 yr, he was placed on carbenoxolone therapy, which allowed him to grow and progress to puberty.

This patient was the only clinically affected member of his family. His father was healthy and had normal serum electrolytes and plasma aldosterone as well as normal 24-h urinary aldosterone excretion. Of the patient’s three sisters, one had died at the age of 4 days from "cerebral hemorrhage," whereas his other two sisters were reportedly healthy.

Case 2

The proband, a 13-yr-old black female, was born by spontaneous vaginal delivery without complication at full term. She presented at 10 days of age with shock and severe hyponatremia [sodium (Na), 110 mmol/L] and hyperkalemia [potassium (K), 8.7 mmol/L]. The diagnosis of PHA was made at 11 months of age, when she was evaluated at New York Hospital (8). During the evaluation, serum sodium was 131 mmol/L, and potassium was 6.5 mmol/L, whereas her urinary sodium was 150 mmol/24 h, despite taking 3 mmol/kg·day sodium. Her plasma aldosterone level and PRA were markedly elevated (9.1 nmol/L and 1.29–28.07 ng/mL·h, respectively). Salivary and sweat sodium were also elevated at 144 and 148 mmol/L, respectively. Her renal and adrenal functions were normal. The family history was notable for hypertension, and the pedigree did not reveal consanguinity.

Case 3

The proband, a 3-yr-old Portuguese female, was born at full term by spontaneous vaginal delivery without complication. At 7 days of age, she presented at St. Barnabas Hospital in New Jersey in a state of shock with severe hyponatremia (Na, 109 mmol/L) and hyperkalemia (K, 8.9 mmol/L). The diagnosis of pseudohypoaldosteronism was based on her extremely elevated plasma aldosterone levels (8.48–142.9 nmol/L) and PRA (5054–8049 ng/mL·h). Her sweat sodium level was higher than normal (67.3 mmol/L; normal, 15.9–45.9). Her parents were third cousins and had normal plasma aldosterone concentrations and PRA.

Case 4

The proband, a 5-week-old Moroccan male, was born by spontaneous vaginal delivery without complications at full term. He presented at 5 weeks of age at the Hospital Universitaire des Enfants Reine Fabiola in Brussels with frequent vomiting and severe dehydration, associated with marked hyponatremia (Na, 115 mmol/L) and hyperkalemia (K, 8.8 mmol/L). His plasma aldosterone concentration was extremely elevated (36 nmol/L), as was his PRA (38.9 ng/mL·h), which led to the diagnosis of pseudohypoaldosteronism. His saliva sodium concentration was 134 mmol/L. His parents were first cousins. There was no family history of hypertension.

Case 5

The proband, a 7-month-old white male, was born by spontaneous vaginal delivery at full term, with the only complication being mild maternal preeclampsia. At 1 month of age, he presented with poor weight gain and failure to thrive. Initial evaluation revealed hyponatremia (Na, 126 mmol/L) and hyperkalemia (K, 5.6 mmol/L). At 2 months of age, he was referred to the Department of Pediatrics, West Virginia University Charleston Division, for further evaluation. This revealed an extremely elevated plasma aldosterone concentration (46.8 nmol/L; normal, 0.22–0.43) and PRA (>998.9 ng/mL·h; normal, 1.1–4.1). There was no history of consanguinity.

Methods

Establishment of permanent cell lines. Epstein-Barr virus-transformed lymphoblast lines were established from all patients and/or their parents, as previously described (37). Cells were harvested in RPMI 1640 medium with 10% FBS and 2 mmol/L glutamine.

Sequencing of genomic DNA. Genomic DNA was isolated from Epstein-Barr virus-transformed lymphoblast lines, as previously described (29). The genomic DNA fragments were amplified by PCR. The sets of primers used for amplifying {alpha}-, ß-, and {gamma}ENaC were described by Chang et al. (35). The genomic DNA fragments of {alpha}ENaC were sequenced directly by the dideoxynucleotide chain termination method, as previously described (32), whereas those of ßENaC and {gamma}ENaC were sequenced directly by Big Dye terminator cycle sequencing (PE Biosystems, Foster City, CA) with an ABI 377 automated DNA sequencer (PE Biosystems, Foster City, CA).

Population study of identified mutations in {alpha}ENaC. An identified base substitution in {alpha}ENaC created a new recognition site for Aci 1 (C/CGC) at position 2086 of the {alpha}ENaC cDNA, whereas the wild-type allele was not cut by this enzyme. We amplified the 440-bp PCR fragment of genomic DNA (cDNA position 1820–2260) of the {alpha}ENaC cDNA from the 5 patients and 42 unrelated control subjects with apparently normal salt conservation. Fifty microliters of the PCR products were digested with 100 U Aci 1 (New England Biolab, Beverly, MA) at 37 C for 16 h and separated on a 2% agarose gel. The normal PCR fragment was cut into 3 fragments (226, 163, and 51 bp) by Aci 1, whereas the PCR fragment containing the mutant allele was cut into 4 fragments (226, 43, 123, and 51 bp).

Patient and control population study of identified amino acid substitutions in ß- and {gamma}ENaC. We studied the frequency of the amino acid substitutions identified in ßENaC and {gamma}ENaC of our patients in 25 of our control subjects by directly sequencing their genomic DNA.

Statistical analysis. The {chi}2 test was employed to examine the difference between the patient group and normal subjects in having concurrent polymorphisms of the {alpha}ENaC cDNA and the MR cDNA.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The results are summarized in Table 2Go. A nonconservative amino acid substitution (A2086->G2086, Thr663->Ala663) was identified in the {alpha}ENaC of the 5 patients, 2 in the homozygous and 3 in the heterozygous form, respectively (Fig. 1Go). This amino acid substitution was also found in a high proportion of 42 unrelated control subjects. The homozygosity and heterozygosity frequencies of the {alpha}ENaC Ala663 were 31% and 64%, respectively.


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  		Table 2. Concurrence of MR and {alpha}ENaC polymorphisms in sporadic PHA and control subjects

 


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  		Figure 1. "Mutant" versus normal {alpha}ENaC DNA sequence in a patient with PHA and in a normal subject.

 
A nonconservative homozygous amino acid substitution (C1006->G1006, Pro336->Ara336) in the ßENaC and 3 homozygous amino acid substitutions (T554->A554, Trp178->Arg178; C1526->G1526, Pro501->Ala501; T1862->G1862, Ser614->Ala614) in the {gamma}ENaC were identified in all 5 of our patients and in all 25 control subjects examined.

Three of the four (75%) patients with multiple tissue resistance to aldosterone had both {alpha}ENaC (heterozygous or homozygous) and MR (homozygous) mutations, whereas only 7% of our controls with apparently normal salt conservation had the same concurrent abnormalities (Table 2Go; P < 0.025).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Frame-shift and stop codon mutations of {alpha}ENaC and a missense mutation of ßENaC resulted in loss of amiloride-sensitive sodium channel activity in PHA patients from autosomal recessive kindreds (35, 36). However, we found none of these mutations in our five sporadic cases of PHA. Instead, we identified a polymorphism located at a position close to the C-terminal of the {alpha}ENaC, which was also present at high frequency in apparently normal controls. A previous report also showed that this polymorphism was present in 49% of a control population in the heterozygous form (38). The proline-rich region of the C-terminal of the {alpha}ENaC that we identified is important for binding to {alpha}-spectrin and for stabilization of the sodium channel in the membrane, suggesting that the above polymorphism might have functional significance (39).

We identified two different amino acid substitutions at the immunogenic domain of the MR in our PHA patients with multiple end-organ resistance to aldosterone, whereas we found no abnormalities in the DNA- or ligand-binding domains; one of these amino acid substitutions was nonconservative (23, 27). The base changes that led to these amino acid substitutions, however, were also present in a substantial proportion of apparently normal individuals and, therefore, should not be sufficient by themselves to cause PHA.

Finally, we identified four amino acid substitutions in the ß- and {gamma}ENaC subunits in all patients and control subjects examined, suggesting that they might have been wrongly sequenced originally or that they are extremely common polymorphisms in the general population.

We have to assume that the {alpha}ENaC amino acid substitutions identified in our patients and significant proportion of control subjects are pathophysiologically insignificant polymorphisms by themselves. Warnock et al. previously described a ßENaC polymorphism that might influence sodium transport (40). We cannot rule out, however, the possibility that they may confer vulnerability in salt conservation, which might be expressed fully only when concurrently present with other genetic defects of the MR or other proteins that participate in sodium homeostasis, such as Nedd 4 (41).

Indeed, we did find an increased co-occurrence of {alpha}ENaC and MR polymorphisms in our patients. Our hypothesis, if true, would be compatible with a sporadic presentation or a digenic or multigenic expression and heredity, as previously described in retinitis pigmentosa (42). In this case, hereditary transmission might be complex and appear as either a dominant and/or a recessive trait with variable penetrance.

We conclude that the amino acid substitutions of the {alpha}ENaC identified in our patients are polymorphisms that do not cause the disease by themselves. We hypothesize, however, that the disease might result from a combination of abnormalities in the {alpha}ENaC, MR, and other molecules important for sodium transport and conservation (31, 32).


   Acknowledgments
 
We thank Drs. M. Naruse and H. Demura (Tokyo Women’s Medical University) for their support.


   Footnotes
 
1 This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japanese Ministry of Education, Science, Sports, and Culture. Back

Received October 28, 1998.

Revised March 31, 1999.

Accepted April 7, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Evidence for Genetic Heterogeneity of Pseudohypoaldosteronism Type 1: Identification of a Novel Mutation in the Human Mineralocorticoid Receptor in one Sporadic Case and No Mutations in Two Autosomal Dominant Kindreds
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2056 - 2059.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
M. Adachi, K. Tachibana, Y. Asakura, S. Abe, J. Nakae, T. Tajima, and K. Fujieda
Compound Heterozygous Mutations in the {{gamma}} Subunit Gene of ENaC (1627delG and 1570-1G{->}A) in One Sporadic Japanese Patient with a Systemic Form of Pseudohypoaldosteronism Type 1
J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 9 - 12.
[Abstract] [Full Text]

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