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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 9-12
Copyright © 2001 by The Endocrine Society

Special Articles

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

Masanori Adachi, Katsuhiko Tachibana, Yumi Asakura, Syuji Abe, Jun Nakae, Toshihiro Tajima and Kenji Fujieda

Department of Endocrinology and Metabolism (M.A., K.T., Y.A.), Kanagawa Children’s Medical Center, Yokohama 232-8555; and Department of Pediatrics (S.A., J.N., T.T., K.F.), Hokkaido University School of Medicine, Sapporo 060-8638, Japan

Address correspondence and requests for reprints to: Masanori Adachi, M.D., Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Minami-ku, Mutsukawa, 2-138-4, Yokohama 232-8555, Japan. E-mail: DZF01210{at}nifty.ne.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The systemic form of pseudohypoaldosteronism type 1 (PHA1) is a rare autosomal recessive disorder with salt-wasting, hyperkalemia, metabolic acidosis, and multiorgan aldosterone unresponsiveness. Recently, this form of PHA1 was found to be caused by the loss-of-function mutations in the gene of each subunit ({alpha}, ß, and {gamma}) of the epithelial sodium channel (ENaC). To investigate the molecular basis of one sporadic Japanese patient with a systemic form of PHA1, we determined the nucleotide sequence of the genes of every subunit of ENaC of this patient. The patient was found to be a compound heterozygote for one base deletion in exon 12 (1627delG) in combination with 1570-1->GA substitution at the 5' splice acceptor site of intron 11 in the {gamma} subunit gene of ENaC. The 1627delG mutation altered a reading frame, resulting in a premature stop codon in exon 12. Messenger RNA from the allele harboring the splice site mutation was not identified by RT-PCR. In conclusion, two novel mutations in the {gamma} subunit gene of ENaC caused systemic PHA1 in the sporadic Japanese patient. Identification of the molecular basis of PHA1 is helpful for early diagnosis and understanding the pathophysiology of the disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PSEUDOHYPOALDOSTERONISM TYPE 1 (PHA1) is a rare inherited disorder characterized by defective sodium transport in the distal nephron and renal salt wasting despite elevated plasma aldosterone levels (Refs. 1 and 2 , and references therein). Two clinically distinct forms of PHA1 have been described (3): a severe autosomal recessive form that is characterized by salt loss from multiple organs, involving the kidney, the distal colon, the salivary glands, and the sweat glands (systemic PHA1) (4, 5, 6); and a less severe autosomal dominant form in which the disease is limited to the kidney (renal PHA1) (3, 7). Both forms of PHA1 present symptoms such as hyponatremia, hyperkalemia, metabolic acidosis, and dehydration within the first week of life (3). Moreover, children with the systemic form often manifest lower respiratory tract illnesses due to the excess volume of airway surface liquid resulting from defective sodium-dependent liquid absorption (8).

Recently, the molecular basis of both forms of PHA1 has been clarified. The systemic PHA1 is caused by the loss-of-function mutations in {alpha}, ß, and {gamma} subunit genes for the amiloride-sensitive epithelial sodium channel (ENaC) (8, 9, 10), and the renal PHA1 is caused by heterozygous mutations of the mineralocorticoid receptor gene (11).

ENaC is proposed to form a heterotrimer composed of three homologous subunits ({alpha}, ß, and {gamma}) (12). Each subunit of ENaC has highly conserved two hydrophobic domains (H1M1 and H2M2), in which M1 and M2 represent membrane-spanning regions, H1 and H2 hydrophobic regions, intracellular C- and N-terminals, and a large extracellular loop (Fig. 1AGo) (12). Sodium transport mediated by this channel is the rate-limiting step for sodium absorption by the epithelial cells that line the distal renal tubule, the distal colon, the ducts of the salivary and sweat glands, and the lung epithelium (13). Thus, the mutations of each subunit gene of ENaC result in the failure of sodium absorption in every target organ, leading to the systemic PHA1.



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  		Figure 1. Mutations in the {gamma} subunit gene of ENaC in the PHA1 patient. A, Schematic representation of the {gamma} subunit of ENaC. The arrows indicate two distinct mutations identified in our study. The 1627delG mutation introduces the premature stop codon (asterisk). Italics denotes the only mutation of the {gamma} subunit gene of ENaC, which was reported previously (10 ). CRD, Cystein-rich domain; H1 and H2, two hydrophobic domains; M1 and M2, two transmembrane domains; P, a pore-forming region involving ion permeation in a short segment preceding the M2 region (25 ). B, Pedigree of family. The half-solid symbol indicate the heterozygous state for 1570-1G->A mutation, and half-shaded symbol indicates the heterozygous state for 1627delG mutation. The asterisk denotes the proband in this family. ND, Not determined. C, In exon 12, a heterozygous G base deletion at nt 1627 was found (arrow). D, The sequence of intron 11 revealed a heterozygous G->A alteration at the intron/splicing junction (arrow). In sequence chromatogram, the antisense strand is shown. Lowercase letters are in intron 11, and uppercase letters are in exon 12.

 
In this report, we describe one sporadic Japanese patient with a systemic form of PHA1 and delineate two novel mutations of the {gamma} subunit gene of ENaC.

To our knowledge, this is the first case of PHA1 caused by compound heterozygous mutations of the {gamma} subunit gene of ENaC.


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

The patient was born at full term and was the second product of healthy, unrelated Japanese parents. The entire course of the pregnancy and the delivery were uneventful. The patient’s birth weight and length were 3.8 kg and 50 cm, respectively. He was referred to our neonatal unit at 7 days of age because of frequent vomiting and severe dehydration. Neither unusual skin pigmentation nor ambiguous genitalia were present.

The initial examination revealed marked hyponatremia (Na, 116 mEq/L), hyperkalemia (K, 8.6 mEq/L), and metabolic acidosis (base excess, -8.0 mEq/L). His plasma aldosterone concentration was extremely elevated [29,740 pmol/L (normal range for neonates, 560–2,800)], as was his PRA [192 mg/L·h (normal range, 0.2–17.5)]. Other endocrine findings were all within normal range, including adequate serum cortisol response (1,290 nmol/L). His renal function was also normal. Based on these clinical and laboratory findings, he was diagnosed as having the systemic form of PHA1. Since then, he has been treated with salt supplementation (NaCl 6.0 g daily) and dietary potassium restriction. Up to the age of 7 yr he required frequent hospital admissions for iv hydration. Also, he had frequent lower respiratory tract illnesses characterized by chest congestion and cough often associated with fever and wheezing. These respiratory symptoms became less severe and less frequent with advancing age. This patient was the only clinically affected member among his family, and his elder sister was healthy (Fig. 1BGo).

PCR and direct sequencing of the {alpha}, ß, and {gamma} subunit genes of ENaC

Informed consent was obtained from the parents for DNA analysis. Genomic DNA was prepared from white blood cells of the patient and his parents using standard techniques. The exons and exon-intron boundaries of genes for the {alpha}, ß, and {gamma} subunits of ENaC were amplified by PCR using oligonucleotide primers described by Chang et al. (9) with a modification (G11 forward, 5'-TTCCTGTGTGAGGCCAACTTGG-3' for amplification of exon 12 of the {gamma} subunit gene). Each PCR using a Perkin-Elmer/Cetus Thermal Cycler (Perkin-Elmer Corp., Norwalk, CT) was performed as: 30 cycles of 60 sec at 94 C for denaturation, 60 sec at 62 C for annealing, and 60 sec at 72 C for polymerization. Each PCR product was purified by 2% NuSieve (FMC Bioproducts, Rockland, ME) gel electrophoresis, and then both strands of products were directly sequenced using an automated DNA sequencer with Taq DyeDeoxy sequencing reagents (PE Applied Biosystems, Inc., Foster City, CA), as described previously (14).

RNA extraction, RT-PCR, and complementary DNA (cDNA) direct sequencing

A lymphoblastoid cell line from the patient was established following Epstein-Barr virus transformation by standard methods. Total RNA was extracted using the RNAzol B kit (Tel-Test, Inc., Friendswood, TX). Specific antisense- primed cDNAs were synthesized from 200–250 ng total RNA in a final volume of 20 mL using a GeneAmp Thermostable rTth Reverse Transcriptase RNA PCR Kit (Perkin-Elmer Corp., Foster City, CA). Using all the reactant containing cDNA, the first PCR was carried out with a set of primers 5'-CAAAGACCTGAACCAGAGATCC-3' (primer A) and 5'-GAGCTCATCCAGCATCTGG-3' (primer B) according to the manufacturer’s protocol (Fig. 2AGo). After chloroform-ethanol precipitation, the first PCR products were subjected to the second PCR reaction with nested primer C (5'-GATCCATCATGGAGAGCCCA-3') and primer B. Primers B and C were designed to encompass the 3' end of exon 11 and the entire exon 12 of the {gamma} subunit gene of ENaC, with a predicted product size of 407 bp (Fig. 2AGo). Conditions for the second PCR were 40 cycles of 60 sec at 94 C, 60 sec at 60 C, and 120 sec at 72 C. The second PCR products were visualized by 2% NuSieve gel electrophoresis. The cDNA band of the patient was purified using Wizard PCR Preps DNA Purification System (Promega Corp., Madison, WI), and then both strands of product were directly sequenced using an automated DNA sequencer, as mentioned above.



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  		Figure 2. RT-PCR analysis of mRNA of the {gamma} subunit gene of ENaC from lymphoblastoid cell line. A, The location of primers for cDNA amplifying. Two mutations identified in this study are denoted by arrows. The site of a premature stop codon introduced by the deletion mutation is indicated by an asterisk. The sequences of the primers are stated in the manuscript. B, Samples from the patient (lanes 1 and 4) and from a normal control (lanes 2 and 5), derived from specific antisense primers, were subjected to 2% NuSieve gel electrophoresis. Lanes 1–3 are the products amplified by primers C–B, and lanes 4–6 by primers A–E. Lane M indicates a DNA size marker øfX174/HincII digest. Lanes 3 and 6 serve as negative (non-RT) control. Samples derived from oligo d(T)16 primer yielded to the essentially identical results (data not shown). C, Nucleotide sequences of the patient’s RT-PCR product. Direct sequencing revealed that this fragment had only the 1627delG mutation derived from the maternal allele.

 
Another set of nested primers was prepared for RT-PCR (Fig. 2AGo). Primer D (5'-GACAGACTTGGCCAAACTCTTG-3') and primer B were used for the first round amplification, and primers A and E (5'-TACGGGGAGCTTCTGGACATG-3') for the second PCR, with a predicted cDNA size of 236 bp. PCR condition was not changed, except for the annealing temperature (57 C) in the second PCR.

Additionally, oligo d(T)16 (Perkin-Elmer Corp.) was also used for priming the RT reaction as the manufacturer’s protocol, followed by the amplification with primers A and B, and then with primers C and B.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Mutational analysis of the {alpha}, ß, and {gamma} subunit genes of ENaC

PCR-direct sequencing of the entire coding regions of the {alpha} and ß subunit genes of ENaC failed to identify any mutations. However, we identified one base deletion (1627delG) in exon 12 (Fig. 1CGo) and a G to A transition, which occurred at the terminal acceptor splice site, flanking the 5' end of exon 12 (1570-1G->A) (Fig. 1DGo) in the {gamma} subunit gene of ENaC. The former one-base deletion (1627delG) altered an open reading frame, resulting in a premature stop codon 166 nucleotides downstream in exon 12. Family analysis revealed that the mother carried the 1627delG mutation and the father carried the 1570-1G->A mutation as a heterozygote, respectively (Fig. 1BGo).

Detection of {gamma} subunit gene mRNA in lymphoblastoid cell line by RT-PCR

Because the alignment of AG at the -2 and -1 positions of the acceptor splice site is well conserved in eukaryotes (15, 16), it is assumed that an abnormal splicing may have occurred because of 1570-1G->A mutation. To assess the effect of this mutation, we performed RT-PCR experiments [one with oligo d(T)16 primer and those with two different sets of specific primers] with the lymphoblastoid cell line. In each experiment, the resulting cDNA band from the patient was identical in size to that from the normal control lymphoblastoid cell line (Fig. 2BGo). Direct sequencing of the patient’s bands revealed only 1627delG mutation (Fig. 2CGo). These findings indicated that mRNA was transcribed from only the maternal allele, not from the paternal allele, because of the splicing junction mutation in the last intron.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our patient manifested severe neonatal-onset salt wasting, hyponatremia, hyperkalemia, elevated plasma aldosterone, and renin activity. He also showed respiratory symptoms after 1 month of age. Recent studies have revealed that airway abnormality in systemic PHA1 is associated with an excess volume of airway surface liquid resulting from defective sodium-dependent liquid absorption (8). Although his respiratory illnesses were suggestive of asthma, he did not show elevated serum IgE levels. Thus, all his symptoms are compatible with systemic form of PHA1.

In this study, we identified two novel heterozygous mutations (1627delG and 1570-1G->A) in the {gamma} subunit gene of ENaC. Family analysis identified that the mother carried the heterozygous 1627delG mutation and the father carried the heterozygous 1570-1G->A mutation, indicating autosomal recessive inheritance.

Until now, several mutations in either the {alpha}, ß, or {gamma} subunit gene of ENaC were identified in the patients with systemic PHA1. In the {alpha} subunit gene of the ENaC, mutations including one or two base deletions leading to frameshift, two different premature stop codons, and deletion of exons 3 and 4 have been described (8, 9, 17). All these mutations are thought to produce truncated protein, resulting in the loss of function of the channel. Additionally, one missense mutation in the M2 domain was reported, recently (17). In the ß subunit gene of the ENaC, one missense (G37S) and two deletion mutations accompanying frameshift have been identified (8, 9). In the {gamma} subunit gene of the ENaC, only one mutation of the 3' splice site mutation (318-1G->A) has been reported in familial patients (Ref. 10 ; Fig. 1AGo). This mutation caused abnormal splicing resulting in the substitution of conserved amino acids and grossly truncated C-terminal (10).

The 1627delG mutation in our patient is located in M2 domain and produces a premature stop codon 166 nucleotides downstream (Fig. 1AGo). Therefore, this mutation eliminates the most of M2 domain and C-terminal intracellular domain, resulting in the loss of channel function. In RT-PCR reaction there exists the expected PCR fragment, including 1627delG mutation. Because of the presence of the premature stop codon, one would expect an absence of cDNA due to mRNA instability or a truncated cDNA. However, it has been reported that introduction of the premature stop codon does not always affect the mRNA transcription in several cases (18, 19, 20). Thus, our results of RT-PCR obtaining expected fragments could be explained.

The other mutation, 1570-1G->A, is located in a terminal exon splice junction. In general, any mutations in consensus splice-site sequences yield to exon skipping and to the activation of cryptic splice sites at a lesser frequency, causing human disease (21, 22, 23). However, mutation of a terminal exon splice junction is rare. Otterness et al. (24) reported a mutation with the G->A transition at the last nucleotide of the final intron/exon junction in the thiopurine methyltransferase gene, in human thiopurine intorelance. In their study, mRNA of thiopurine methyltransferase from the mutated allele was not identified by RT-PCR analysis, presumably due to mRNA instability resulting either from activation of a cryptic splice site within intron or from creation of a novel splice site. Similarly, mRNA from the allele harboring the 1570-1G->A mutation was not detected in our study. Thus, we presume that this mutation might cause aberrant splicing and inhibit the normal mRNA transcription.

In conclusion, we reported the first sporadic patient with the systemic form of PHA1 caused by compound heterozygous mutations of the {gamma} subunit gene of ENaC. Identification of the molecular basis of this disorder is helpful for early diagnosis, clinical management, and understanding the pathophysiology of PHA1.


   Acknowledgments
 
We are grateful to Drs. T. Shigeta and S. Mizutani (Department of Virology, National Children’s Medical Research Center, Tokyo, Japan) for preparing generously the lymphoblastoid cell line of the patient for us.

Received March 1, 2000.

Revised August 29, 2000.

Accepted September 13, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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