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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 227-231
Copyright © 2004 by The Endocrine Society

A Novel Nonsense Mutation of the Mineralocorticoid Receptor Gene in a Swedish Family with Pseudohypoaldosteronism Type I (PHA1)

A.-M. Nyström, M.-L. Bondeson, N. Skanke, J. Mårtensson, B. Strömberg, J. Gustafsson and G. Annerén

Departments of Genetics and Pathology (A.-M.N., M.-L.B., J.M., G.A.) and Women’s and Children’s Health (B.S., J.G.), Uppsala University, S-751 85 Uppsala, Sweden; and Department of Pediatrics (N.S.), Central Hospital of Eskilstuna, S-637 88 Eskilstuna, Sweden

Address all correspondence and requests for reprints to: Professor Göran Annerén, M.D., Department of Clinical Genetics, Uppsala University Children’s Hospital, S-751 85 Uppsala, Sweden. E-mail: goran.anneren{at}genpat.uu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Pseudohypoaldosteronism type I (PHA1) is a condition associated with salt wasting leading to dehydration, hypotension, hyperkalemia, and metabolic acidosis. Sporadic cases and two familial forms, one autosomal dominant and one autosomal recessive form, have been described. The autosomal dominant or sporadic form manifests milder salt wasting that remits with age. Mutations in the gene encoding the mineralocorticoid receptor (MR) have been identified in patients with the autosomal dominant inheritance. However, recent studies suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that additional genes might be involved. We report on the study of 15 members of a Swedish five-generation family with the autosomal dominant form of PHA1. Interestingly, neuropathy was found in two of five affected individuals. A novel heterozygous nonsense mutation C436X in exon 2 was identified in the index patient by linkage analysis, PCR, and direct sequencing of the MR gene. Analysis of the family demonstrated that the mutation segregated with PHA1 in the family. It is unclear whether the neuropathy is associated with the mutation found. Our results together with previously published data suggest that loss-of-function mutations of the MR gene located at 4q31.1, commonly are associated with the autosomal dominant form of PHA1.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PSEUDOHYPOALDOSTERONISM TYPE I (PHA1) is a rare inherited disease that appears in early life with salt wasting, failure to thrive, dehydration, hypotension, hyperkalemia, and metabolic acidosis. Despite symptoms correlating with low hormonal levels and high urinary and plasma concentration of aldosterone as well as elevated plasma renin activity is present. PHA1 is also referred to as mineralocorticoid resistance, a name derived from the renal resistance and/or resistance of other mineralocorticoid target tissues to aldosterone. The majority of cases are sporadic, but inherited autosomal recessive or dominant forms are also reported (1, 2). The recessive form is typically severe, and may even be lethal and persists into adulthood. It is characterized by severe multiple organ resistance to aldosterone. The affected organs include the kidneys, colon, and sweat and salivary glands. The autosomal dominant and the sporadic forms frequently display renal resistance to aldosterone, manifest milder symptoms, and can even be asymptomatic. They are characterized by salt wasting as well as hyperkalemia, metabolic acidosis, and elevated plasma renin activity and aldosterone levels. Clinically, the symptoms remit with age, whereas the elevated hormone levels persist.

PHA1 is not only heterogeneous regarding the pathogenesis, clinical, and biochemical presentation but also with regard to its genetic causes. The autosomal recessive form is caused by loss-of-function mutations in the genes encoding the {alpha}-, ß-, and {gamma}-subunits of the amiloride-sensitive luminal sodium channel (ENaC), which is responsible for sodium reabsorption (3, 4, 5, 6, 7, 8, 9). The {alpha}-subunit is encoded on chromosome 12p13.1, whereas the ß- and {gamma}-subunits are encoded on chromosome 16p12.2–13.11 (10, 11). The dominant and sporadic forms of PHA1 have been reported to be associated with inactivating mutations of the mineralocorticoid receptor (MR) gene on chromosome 4q31.1 (12, 13, 14, 15, 16, 17, 18). The MR gene consists of 10 exons, in which the first two exons (1{alpha} and 1ß) are composed of 5' untranslated sequences. The gene, which belongs to the steroid receptor superfamily, encodes a protein of 984 amino acids, which starts in exon 2 (19, 20).

However, there are other studies that suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that genes additional to MR might be involved (14, 21, 22, 23, 24). Additional studies of PHA1 and the genetic defects associated with the disorder are, therefore, motivated and may contribute to an increased knowledge about the putative genetic heterogeneity as well as the aldosterone system.

In this study, we analyzed 15 members of a Swedish five-generation family with PHA1 by using linkage analysis, PCR, and direct sequencing of the MR gene. We present the identification of a novel nonsense mutation, C436X, of the MR gene causing the autosomal dominant form of PHA1, suggesting that this form commonly is associated with loss-of-function mutations in the MR gene.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All clinical investigation and genetic analyses were conducted in accordance with the guidelines in the Declaration of Helsinki and with approval from the ethical committee of Uppsala University. Informed consent was obtained from all family members.

Subjects

II:1 born in 1939. This subject was a healthy half-sister to the great grandfather of the index patient. She had no problems with vomiting or salt losing during the neonatal period. Normal serum levels of sodium, aldosterone, and renin were found later in life.

II:2 born in 1925. This was the great-grandfather of the index patient. This subject died from a stroke in 1999, which explains why the case history is incomplete. There is no known history of vomiting, excess drinking, poor weight gain, or need of extra salt during childhood according to the relatives.

III:2 born in 1949. This subject was the maternal grandmother of the index patient. She had severe problems with vomiting and poor weight gain during early childhood and needed extra salt. No laboratory analyses have been performed to confirm the diagnosis. She has presently no symptoms of PHA1 and has never had any clinical signs of neuropathy.

IV:2 born in 1971. This was the mother of the index patient. She also had severe problems with vomiting and poor weight gain during early childhood and needed extra salt. At the age of 24 yr, after her son was diagnosed, she was also found to have PHA1. She had elevated serum levels of aldosterone (1540 pmol/liter; reference,<440 pmol/liter) and renin (0.97 pkat/liter; reference, 0.17–0.43 pkat/liter). She presently has no symptoms of PHA1 and has never had any clinical signs of neuropathy.

V:1 born in 1995. This was the index patient. The boy was born prematurely after 33 wk of gestation by cesarean section performed due to prenatal growth retardation. His birth weight was 1500 g. He had full Apgar score and an uneventful perinatal course. At 3 wk of age, he presented with failure to thrive and a low serum level of sodium was found. The serum level of potassium was normal. At 4 months of age, an elevated serum level of aldosterone (11,200 pmol/liter; reference, <440 pmol/liter) and increased renin activity (15 nmol/ml·h; reference, 0.3–2.0 nmol/ml·h) were noted. Because of the clinical and laboratory findings and the family history, an autosomal dominant form of pseudohypoaldosteronism (PHA1) was diagnosed. The patient has continuously been treated with extra doses of sodium chloride, presently 1 g six times daily. At 7 yr of age, the boy is growing at -2 SD according to the Swedish standard (25). He has muscular weakness and weak deep tendon reflexes but is mentally normal. The serum levels of sodium, potassium, and chloride as well as serum aldosterone are normal. Urinary steroid profile shows a relatively low excretion of steroids [cortisol-cortisone metabolites (6 µmol/24 h; reference, 4–20 µmol/24 h); androgens (1.5 µmol/24 h; reference, 1–8 µmol/24 h), pregnanetriol (0.2 µmol/24 h; reference, <1 µmol/24 h)] (26). The quotient cortisol/cortisone is somewhat low. Aldosterone metabolites in urine has not been analyzed. Because of the muscular weakness, a neuromuscular investigation was performed. Normal serum level of creatine kinase and a normal muscle biopsy were found. An examination of the sensory and motor conduction velocities of his peripheral nerves, however, revealed a severe demyelinating neuropathy.

V:2 born in 1996. This subject was the sister of the index patient. She was born after 40 wk of gestation and had a normal birth weight. Immediately after birth she developed problems with vomiting. Low serum levels of sodium and elevated levels of aldosterone (5020 pmol/liter; reference, <440 pmol/liter) and renin (279 ng/liter; reference 4–46 ng/liter) were noted, and the diagnosis of PHA1 was confirmed at the age of 1 wk. She has been treated with extra sodium chloride from birth and presently has almost no problems from the disease. This girl was also found to have a muscular weakness and weak deep tendon reflexes. Therefore, she also underwent a peripheral neurography, which showed the same kind of demyelinating neuropathy as in the index patient.

V:3 born in 1998. This subject was the healthy younger brother of the index patient. The boy had no problems with vomiting or salt losing during the neonatal period. Normal serum levels of sodium, aldosterone, and renin have been found.

Methods

DNA extraction and genotyping. Genomic DNA was extracted from peripheral blood leukocytes using standard techniques. The following polymorphic markers were used for genotyping; D4S1586, D4S3014, D4S3008, D4S1548, D12S99, D12S413, D16S403, D16S412, and D16S420. PCR was performed on 25 ng genomic DNA, 1x PCR buffer (Applied Biosystems Roche, Foster City), 3 nmol of each deoxynucleotide triphosphate (Amersham Biosciences, Uppsala, Sweden), 2.5 pmol of each primer (forward primers were 5', end labeled with fluorescent), and 0.8 U AmpliTaq Gold polymerase (Applied Biosystems, Roche) in a total volume of 15 µl. The first cycle of amplification was run with the following conditions: 94 C for 10 min, 55 C 30 sec, and 72 C 30 sec. Thereafter, 28 cycles followed at 30 sec at 94 C, 30 sec at 55 C, and 30 sec at 72 C, except for the last cycle, which consisted of a 6-min extension. Alleles were separated by a 4% PAGE on an ABI 377 with TAMRA GS-350 (PE Applied Biosystems, Foster City, CA) as size standard. Signal analysis and genotype determination was automated using GENESCAN 3.0 (PE Applied Biosystems) and GENOTYPER 2.5 (PE Applied Biosystems).

Mutational analysis

Primers were designed to cover the entire coding region and the intron-exon boundaries of the MR gene according to published sequences (19). Details of the primers are shown in Table 1Go. The MR gene of the index patient was amplified by using 600 ng of genomic DNA, 1x PCR buffer (Applied Biosystems Roche), 10 nmol of each deoxynucleotide triphosphate (Amersham Biosciences), 10 pmol of each primer, and 5 U of AmpliTaq Gold polymerase (Applied Biosystems Roche) in a total volume of 50 µl. An initial denaturation step of 10 min at 94 C was followed by 38 cycles of 30 sec at 94 C, 30 sec at 52–58 C, 1 min at 72 C, and one cycle of 7 min at 72 C. The PCR products were purified using the QIAquick PCR purification kit (QIAGEN, Hilden, Germany) before sequencing was carried out using the ABI PRISM BigDye Primer version 3.0 Cycle sequencing ready reaction kit (PE Applied Biosystems), according to the manufacturer’s instructions. The reaction products were analyzed on an ABI 377 sequencer. Genomic DNA from additional family members and one control were amplified using the primer pair 2F_1183 and 2R_1466 (Table 1Go). The PCR products were digested with restriction endonuclease MboI (Amersham Biosciences).


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  		TABLE 1. Primer pairs used to amplify the coding sequence of MR

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Initially, a linkage analysis was performed of the PHA1 family to investigate linkage to previously identified genes involved in PHA1 on chromosomes 4q31.1, 12p13.1, and 16p12.2–13.11. The linkage analysis was performed with the markers, D4S1586, D4S3014, D4S3008, D4S1548, D12S99, D12S413, D16S403, D16S412, and D16S420. No linkage was observed to chromosomes 12 and 16, which is consistent with the observation that mutations in the ENaC gene are associated with the autosomal recessive form of PHA1. However, genotyping of chromosome 4 showed that the affected individuals shared the same haplotype for the markers throughout the region (Fig. 1Go). This finding thus suggested that the previously reported MR gene could be the disease-causing gene also in this family. PCR analysis and direct sequencing on both strands of the coding region of MR including the intron-exon boundaries were performed in the index patient (V:1). The DNA sequencing analyses revealed a novel mutation 1308T>A at codon 436 in exon 2 and two previously reported polymorphisms, -2G>C present in a heterozygous state and 722C>T (A241V) present in a homozygous state (23, 27). The mutation introduces a premature stop codon (TGA), which replaces the wild-type Cys (TGT) in exon 2. The mutation creates a new restriction site for MboI. Restriction enzyme digestion of PCR fragments spanning the mutation in exon 2 demonstrated that the mutation segregates with PHA1 in the family, whereas it was absent in a normal control and unaffected family members (Fig. 2Go).



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  		FIG. 1. Pedigree structure and haplotypes for the family. Females are designated by circles and males by squares. Affected individuals are indicated by blackened symbols and deceased by diagonal lines. Genotypes for markers D4S1586, D4S3014, D4S3008, and D4S1548 are shown, and the gene encoding MR (locus NRC32) is placed in relation to the markers according to the map of the Ensemble Genome Database project (http://www.ensembl.org/). The disease-associated haplotype is indicated by black bars.

 


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  		FIG. 2. Mutation analysis of C436X by restriction analysis showing segregation of the mutation in the family. PCR products spanning the mutation in exon 2 were digested with MboI. The heterozygous mutation creates a MboI site, resulting in 156- and 128-bp products, whereas the wild-type allele remains undigested (284 bp). The patients are denoted as in Fig. 1Go. An unrelated individual was used as control (C). As a marker, a 50-bp ladder was used.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Pseudohypoaldosteronism is a rare disease occurring either as sporadic or familial forms. Several sporadic cases as well as cases with the autosomal dominant or recessive forms have been studied to elucidate the mechanism behind the disease. Although mutations in the ENaC and MR genes have been found in some cases, the index case found in 1958 by Cheek and Perry (28) together with a few other patients still remain unexplained.

Here, we describe a Swedish family, with the autosomal dominant form of PHA1, that was studied to investigate the genetic defect associated with PHA1 in this particular family. A novel heterozygous nonsense mutation, C436X, in exon 2 of the MR gene was identified (Fig. 3Go). The MR gene belongs to the steroid receptor superfamily. The N-terminal part is the least conserved region among the family members and usually contains a transactivating function. The central domain is responsible for DNA binding and dimerization and is the most conserved part (94% identity with the glucocorticoid receptor). The C-terminal part shows 57% identity with the glucocorticoid receptor and contains the ligand-binding domain (19, 29). The mutation C436X reported here results in a truncated protein with a complete abrogation of the DNA- and hormone-binding domains.



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  		FIG. 3. Structure of the MR gene with mutations associated with PHA1 described to date. Top, previously found mutations (12 13 14 15 16 ); bottom, mutation of codon 436 found in this study. Nucleotide and codon numbering is according to Arriza et al. (19 ) and den Dunnen and Antonarakis (33 ) (GenBank accession no. M16801, beginning at the initiation codon for translation). Hatched box (exon 2) encodes the immunogenic transactivating domain. Black boxes (exons 3 and 4) encode the DNA-binding domain, and striped boxes (exons 5–9) encode the hormone-binding domain.

 
The clinical characteristics of the family are in agreement with the description of the autosomal dominant form of PHA1 (1, 2). However, there seems to be an individual variation of the symptoms in this family, even though the affected members carry the same mutation. This phenotypic difference within PHA1 families carrying the same mutation has also previously been reported (15, 16).

The index patient described here as well as his sister presents demyelinating neuropathy, which to the best of our knowledge has not previously been described as a feature of PHA1. The etiology behind their neuropathy is unclear, but because the grandmother and mother of the affected children did not have any signs of neuropathy, it seems unlikely to be associated with the mutation, although it cannot be excluded that the neuropathy is associated with the mutation and that the variation in clinical symptoms of neuropathy is due to reduced penetrance.

Mutational analysis of the MR gene has previously been performed in several patients with autosomal dominant and sporadic forms of PHA1. Previous reports have identified 13 different loss-of-function mutations in the MR gene in patients with sporadic or autosomal dominant forms of PHA1 (Fig. 3Go) (12, 13, 14, 15, 16). Interestingly, the MR gene is one example in which activating and inactivating mutations causes distinct hereditary disorders because a gain-of-function mutation that causes early-onset hypertension that is markedly exacerbated in pregnancy has also been found (30).

In several studies of both dominant kindreds and sporadic forms, no mutations in the MR gene were identified. It was, therefore, proposed that additional genes might be involved in the pathogenesis of PHA1. However, it cannot be excluded that these patients present with mutations in the regulatory regions of the MR gene, which were not identified by the analyses performed. It has also been proposed that naturally occurring polymorphisms in the {alpha}ENaC and MR genes could influence the salt conservation negatively if they are present simultaneously or together with other genetic defects in other proteins (31, 32). To address these questions, the use of linkage analysis may be a useful approach to find the mechanism behind the disease in PHA1 families with no detectable mutations in the MR gene.

Here, we have reported on the identification of a novel nonsense mutation in a family with the autosomal dominant form of PHA1 that together with previously published data demonstrate the involvement of the MR gene in the autosomal dominant form of PHA1. Taken together, the 14 identified mutations in the gene described so far suggest that the autosomal dominant form of PHA1 frequently is associated with haploinsufficency of MR.


   Footnotes
 
This work was supported by grants from the Beijer Foundation and the Marcus Borgström Foundation.

Abbreviations: ENaC, Amiloride-sensitive luminal sodium channel; MR, mineralocorticoid receptor; PHA1, pseudohypoaldosteronism type I.

Received May 5, 2003.

Accepted September 29, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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