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Phenotype and Genotype Analysis in Chinese Patients with Gitelman’s Syndrome

Division of Nephrology (S.-H.L., S.-S.Y., Y.-J.H., C.-J.C.), Department of Medicine, Tri-Service General Hospital, Neihu 114, Taipei, Taiwan; Division of Nephrology (J.-C.S.), Department of Medicine, Kaohsiung Army General Hospital, Lin-Ya 802 Kaohsiung, Taiwan; and Department of Biochemistry (C.-C.H.), Neihu 114 National Defense Medical Center, Taipei, Taiwan

Address all correspondence and requests for reprints to: Shih-Hua Lin, M.D., Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Number 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. E-mail: shihhualin{at}yahoo.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Inactivation mutations of the luminal thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubules or the basolateral chloride channel (CLCNKB) in the distal nephron are the most common genetic mutations in Gitelman’s syndrome (GS) or Bartter’s syndrome (BS). We conducted clinical and molecular studies in Chinese patients with GS or BS. Twenty patients with chronic hypokalemia (15 males and five females, age 25 ± 7 yr) from 15 unrelated Chinese families were investigated. All had renal K⁺ wasting, metabolic alkalosis, and normotension. The urinary calcium excretion rate was used to distinguish between BS or GS on clinical grounds. Clinical symptoms and biochemical studies were recorded. Molecular analysis included PCR single-strand confirmational polymorphism, direct sequencing of both the NCC and CLCNKB genes, and restriction fragment length polymorphism. Sixteen patients had a clinical diagnosis of GS with hypocalciuria and four BS without hypocalciuria. Four of these 20 patients did not have hypomagnesemia. The males had severe hypokalemia [1.9 ± 0.4 mEq/liter (mmol/liter)] with paralytic episodes, whereas females had moderate hypokalemia [2.6 ± 0.2 mEq/liter (mmol/liter)] and less severe symptoms. There were no mutations detected in CLCNKB. Twelve NCC mutations, including six novel mutations and nine recurrent ones, were identified. Allele frequency of the detected NCC mutations was 3% in 100 healthy subjects. Some GS patients with NCC mutations may have normocalciuria and/or normomagnesemia. Gender differences may account for phenotype variability. Screening of these identified NCC mutations remains the gold standard for the diagnosis of GS.

	Introduction

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IN 1962, BARTTER et al. (1) first described two normotensive patients who had hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism, blunted response to the pressor effects of angiotensin II, and hyperplasia of the juxtaglomerular apparatus [now called Bartter’s syndrome (BS)]. In 1966, Gitelman et al. (2) described three adult female patients with BS-like symptoms accompanied by hypomagnesemia and hypocalciuria [now called Gitelman’s syndrome (GS)]. In 1992, Bettinelli et al. (3) reported that the molar ratio of urinary calcium to creatinine (Cr) as an index of urine urinary calcium rate index can help to distinguish BS from GS. With the advent of molecular techniques, GS is most associated with inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive NaCl cotransporter (NCC) on the apical membrane of distal convoluted tubules (DCTs). In contrast, in BS, inactivation mutations are found in genes encoding the sodium (Na⁺), potassium (K⁺), 2 chloride (Cl^–) cotransporter (NKCC2), the luminal potassium channel, the basolateral chloride channel (CLCNKB), barttin (Bartter’s syndrome with sensorineural deafness), and the calcium-sensing receptor in the thick ascending loop of Henle (4, 5). Nevertheless, clinical features of GS also occurred in patients who have mutations in the CLCNKB (6, 7).

Although an increasing number of patients with either GS or BS have been identified, clinical and molecular studies have not yet been reported for adult Chinese patients with GS or BS. Therefore, we performed this study to investigate the clinical, biochemical, and genetic characteristics of 20 chronic normotensive and hypokalemic patients from 15 unrelated Chinese families. We identified 12 NCC gene mutations but did not find a mutation in the CLCNKB gene. Some patients with hypokalemia and mutations in NCC did not have hypomagnesemia or hypocalciuria. Moreover, in our male patients with GS, more severe muscle weakness and paralysis were important features.

	Subjects and Methods

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The study protocol was approved by the Ethics Committee on Human Studies at Tri-Service General Hospital, National Defense Medical Center (Taiwan, R.O.C.). The subjects were given a detailed description of the study before they provided informed consent.

Subjects

The study group consisted of 20 patients (15 males and five females, age 25 ± 7 yr) belonging to 15 unrelated families. Data from three of these families (families F, H, and I) were reported previously (8, 9). All had persistent hypokalemia [<3.5 mEq/liter (mmol/liter)] associated with renal K⁺ wasting, persistently high rates of urinary Na⁺ and Cl^– excretion, and normal blood pressure. They did not take laxatives or diuretics and claimed no alcohol or drug abuse. Other extrarenal and renal causes of hypokalemia and transcellular shift of K⁺ such as the use of bronchodilators, thyrotoxic periodic paralysis, and familial periodic paralysis were also excluded. Using the diagnostic criteria of Bettinelli et al. (3), a clinical diagnosis of GS was made if hypocalciuria [urinary Ca²⁺ to Cr ratio < 0.04 mg/mg (<0.1 mmol/mmol)] and/or hypomagnesemia [<1.6 mg/dl (<0.65 mmol/liter)] with renal Mg²⁺ wasting were present. A clinical diagnosis of BS was made if hypocalciuria was not present.

Clinical symptoms, biochemical features, and molecular analysis for NCC and CLCNKB mutation were investigated in these patients.

Clinical symptoms

Clinical symptoms include general, musculoskeletal, renal, gastrointestinal, cardiovascular, and neurological symptoms as previously described (10). In the general symptom category, there was fatigue, dizziness, fainting, and exercise intolerance. Musculoskeletal symptoms included weakness, muscle stiffness or pain, muscle cramps, carpopedal spasm/tetany, and paralysis. Renal symptoms included nocturia, polyuria, polydipsia, thirst, enuresis, and salt craving. Gastrointestinal symptoms included vomiting, constipation, and abdominal pain. Cardiovascular symptoms included palpitation and chest pain. Neurological symptoms included paresthesia and tremor.

Biochemical features

Blood was obtained at rest for routine biochemistry tests, and a spot urine was collected when each patient was first admitted to the hospital. Venous blood gases were measured by an ABL 510 (Radiometer, Copenhagen, Denmark). Biochemical values included Cr, blood urea nitrogen, ionized calcium, inorganic phosphate, Mg²⁺, Na⁺, K⁺, and Cl^–. They were determined by automated methods (AU 5000 chemistry analyzer; Olympus, Tokyo, Japan).

Mutation analysis

Genomic DNA isolation and PCR. Genomic DNA was isolated and purified from peripheral blood of the patients and family members and used for PCR amplification of individual exons of the SLC12A3 (National Center for Biotechnology Information no. NM-000339) and CLCNKB (National Center for Biotechnology Information no. NM-000085). For NCC mutations, 26 pairs of oligonucleotide primers were generated to amplify all 26 exons according to data obtained from Simon et al. (11). PCRs were performed in a 25-µl volume containing 100 ng genomic DNA, 0.4 µM primers, 0.25 mM deoxynucleoside triphosphates, and 2.5 µl 10x Taq buffer [100 mmol/liter Tris-HCl (pH 8.4), 100 mmol/liter (NH₄)₂SO₄, 100 mmol/liter KCl, 22.5 mmol/liter MgCl₂, 0.1% gelatin, 1% Triton X-100, and 2 U Taq polymerase]. PCR was performed using standard conditions with an initial denaturation step at 94 C for 5 min subsequently followed by 30 cycles with denaturation at 94 C for 40 sec, annealing at 60 C for 40 sec, and elongation at 72 C for 40 sec.

To study the CLCNKB mutations, 19 pairs of oligonucleotide primers were generated to amplify all 19 exons of the CLCNKB gene by PCR as previously described (12). PCR-amplified coding regions as well as exon-intron boundaries were sequenced. The PCR conditions for genomic amplification included denaturation at 94 C for 5 min and 30 amplification cycles performed at 94 C for 40 sec, 55 C for 40 sec, and 72 C for 40 sec.

Single-strand confirmational polymorphism (SSCP) analysis and sequencing. DNA samples were amplified by PCR for SSCP as described above. The PCR products were mixed with 10 ml PCR product and 50 ml loading dye (95% formamide, 20 mM EDTA, 0.05% bromophenol blue, and 0.05% xylene cyanol). The samples were denatured in boiling water for 10 min and placed on ice immediately. Electrophoresis was performed on 15% polyacrylamide gel (29:1 acrylamide-bisacrylamide) and 0.5x Tris-borate-EDTA electrophoresis buffer [54 mM Tris, 54 mM boric acid, and 1.2 mmol/liter EDTA (pH 8.3)] at 5 mA for 24 h at 4 C. The gels were then stained by ethidium bromide. The SLC12A3 and CLCNKB exons resulting in SSCP shifts were purified for direct sequence analysis by PCR with identical oligonucleotides as used for PCR-SSCP analysis. Amplified DNA fragments were isolated from agarose gels, using the freeze-squeeze method, and subsequently used as template in PCR cycle sequence reactions in the presence of dye-dideoxy terminators. The reaction conditions were those supplied by the manufacturer (PerkinElmer ABI, Foster City, CA) and analyzed on an ABI 377 automated DNA sequencer (PerkinElmer ABI).

Restriction fragment length polymorphism (RFLP) analysis. RFLP analysis of the mutated exons of NCC was performed as follows. PCR-amplified DNA fragments containing the locus mutated in these family members were digested with the restriction enzyme, and electrophoresis was carried out on 2% agarose gel. The PCR samples were from the GS family members and 100 unrelated healthy subjects.

Statistical analyses

The data in the male and female patients are expressed as mean ± SD. The Student’s unpaired t test and ² test were used to compare the differences between male and female patients. Differences were considered significant when P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical symptoms

As shown in Table 1, muscle paralysis, weakness, cramps, tetany, palpitation, paresthesias, and dizziness were the most common symptoms. Of note, muscle paralysis was usually the primary presenting symptom in affected males. Dizziness, palpitation, and tetany were common symptoms in females. One male (patient 2) and one female (patient 12) were virtually asymptomatic. All patients had normal blood pressure. All the unaffected family members were asymptomatic.

The biochemical features in these 20 patients are summarized in Table 1. All had metabolic alkalosis [pH ranged from 7.42–7.52, and their HCO₃^– concentration ranged from 26.5–35.0 mEq/liter (mmol/liter)]. Their plasma K⁺ concentration was 1.5–3.0 mEq/liter (mmol/liter) (normal, 3.5–5.0 mEq/liter (mmol/liter)], and plasma Mg²⁺ concentration was 0.7–2.2 mg/dl (0.29–0.92 mmol/liter) [normal, 1.6–2.4 mg/dl (0.65–1.0 mmol/liter)]. Their calcium excretion rate varied from a very low to normal value [urine Ca²⁺ to Cr ratio ranged from 0.01–0.09 mg/mg (0.01–0.24 mmol/mmol)]. Sixteen patients had a tentative clinical diagnosis of GS with hypocalciuria, and four were classified as BS because they did not have hypocalciuria [urine Ca²⁺ to Cr ratio from 0.05–0.09 mg/mg (0.13–0.24 mmol/mmol)]. One male patient (patient 1) and one female patient (patient 6) with a clinical diagnosis of GS did not present with hypomagnesemia. Two male patients with a clinical diagnosis of BS did not have hypomagnesemia. Of note, patient 19 had a low glomerular filtration rate because his serum Cr was 1.8 mg/dl (160 µmol/liter) on admission, and it remained elevated with extracellular fluid repletion. This patient also had bilateral renal cysts on renal sonography and typical tubulointerstitial nephritis and renal tubule vacuolization on renal biopsy. All 20 patients were treated with oral KCl supplements [48–96 mEq (mmol)/d] and spironolactone (50–100 mg/d). Their plasma K⁺ values rose to around 2.5–3.5 mEq/liter (mmol/liter). Oral Mg²⁺ supplementations with magnesium oxide 1000 mg daily were given to the patients with hypomagnesemia. Their plasma Mg²⁺ concentration was maintained around 1.2–1.7 mg/dl (0.49–0.70 mmol/liter). All the unaffected family members had normal plasma electrolyte concentrations, and they did not have hypocalciuria.

Mutation analysis of NCC and CLCNKB genes

Amplification, SSCP screening, and direct sequencing of the NCC and CLCNKB genes revealed that 12 NCC mutations, including six novel mutations (H90Y, S283Y, 971InsACCGAAAATTTT, W844stop, R871H, and R928C), were identified despite no detected mutations in CLCNKB (Table 1). Fifteen patients had compound heterozygous mutations, one male and two female patients had a heterozygous mutation, and two male patients had a homozygous mutation (Figs. 1 and 2). One patient (patient 14) had three NCC mutations. Because nine mutations including T60M, H90Y, T163M, 971InsACCGAAAATTTT, R642C, S710stop, R871H, R928C, and R959frameshift were found in at least two unrelated families, it is possible that these mutations are common mutations in Chinese patients with GS. A polymorphism with an adenosine to guanine single-base substitution at nucleotide 372 (A372G) in exon 2, a guanine to cytosine substitution at nucleotide 979 (G979C) in exon 6, and a cytosine to thymine at nucleotide 2148 (C2148T) in exon 17 resulted in no change in alanine at codon 122 in patients 3, 5, and 8, glycine at codon 264 in patients 3, 5, 6, and 11, and leucine at codon 714 in patient 8, respectively.

View larger version (31K): [in this window] [in a new window]   FIG. 1. Direct sequencing and restriction analysis of PCR fragments of exon 1 for NCC mutations in family A. A, Arrow indicates the mutant bases (C274T). Top row indicates wild-type control. B, Male and female are indicated by squares and circles, respectively. Filled symbols represent affected individuals. DNA of the individuals bearing the homogeneous H90Y mutation yields one fragment (334 bp) because the mutation abolishes an RsaI restriction site.

View larger version (33K): [in this window] [in a new window]   FIG. 2. Direct sequencing and restriction analysis of PCR fragments of exons 3 and 21 for NCC mutations in family C. A, Arrow indicates the mutant bases (C494T in exon 3 and G2538A in exon 21). Top row indicates wild-type control. B, Male and female are indicated by squares and circles, respectively. Filled symbols represent affected individuals. DNA of the individuals bearing the T163M mutation yields one fragment (205 bp) because the mutation abolishes a BceAI restriction site. DNA of the individuals bearing the W844stop mutation yields two fragments (268 and 179 bp) with HinfI restriction enzyme.

The NCC gene mutations that we identified were also evaluated in 100 unrelated healthy subjects using RFLP analysis with different restriction enzymes (Table 2). RFLP analysis for the 12 above-mentioned mutations revealed heterozygous T60M in one, T163M in one, R959frameshift in one, and R928C in three of the 100 unrelated healthy subjects. The overall incidence of positive heterogenous mutation was approximately 3% (1 + 1 + 1 + 3/100 x 2).

We did not find evidence of a genotype-phenotype correlation in patients with NCC mutations. However, male patients had more profound hypokalemia [1.9 ± 0.4 vs. 2.6 ± 0.2 mEq/liter (mmol/liter), P < 0.05] compared with female patients despite no significant difference in their plasma HCO₃^– concentration [29.6 ± 2.1 vs. 30.5 ± 3.0 mEq/liter (mmol/liter)], plasma Mg²⁺ concentration [1.4 ± 0.3 vs. 1.1 ± 0.5 mg/dl (0.58 ± 0.13 vs. 0.46 ± 0.21 mmol/liter)], and urinary calcium excretion rate [0.03 ± 0.02 vs. 0.01 ± 0.01 mg/mg (0.08 ± 0.07 vs. 0.04 ± 0.03 mmol/mmol)] (Table 3).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

To date, more than 100 different mutations including missense, nonsense, frameshift, deletion, insertion, and splice site mutations have been identified in patients with GS (11, 13, 14, 15). The mutations are located throughout the coding sequence of the NCC gene, but most of these mutations are most frequently found in the intracellular domains of the protein (11, 17). Missense mutations are the most common reported abnormality. In this report, 12 mutations were found in Chinese patients with GS including eight missense, two nonsense, one deletion, and one insertion type. Among these mutations, nine of 12 resided in the intracellular domain, and six of 12 was localized in the intracellular cytoplasmic carboxyl terminus (Fig. 3). Consistent with the previous reports, compound heterozygosity having two different mutations on the two alleles for NCC was the most common inheritance pattern in these Chinese patients.

View larger version (24K): [in this window] [in a new window]   FIG. 3. Schematic diagram of the NCC and mutations in Chinese GS patients. The NCC is represented as 12 transmembrane domain protein with intracytoplasmic amino and carboxyl termini. The sites of mutations in exons are denoted by arrows.

Salt craving, nocturia, muscle weakness, tetanic episodes, and paresthesia have been reported to be the most frequent symptoms (10). Of interest, muscle paralysis is the primary presentation in all males except two with NCC mutations in this study in contrast to approximately 6% of patients with GS manifesting hypokalemic paralysis reported by Cruz et al. (10). In fact, many Asian patients with GS initially present with paralysis (21, 22). The reason why Chinese male patients have a higher incidence of muscle paralysis is unclear. In addition to the severe degree of hypokalemia, racial differences may be one of the contributory factors based on the greater tendency to develop hypokalemic periodic paralysis in Chinese populations (23, 24).

We did not find a genotype-phenotype correlation in Chinese patients with NCC mutations. However, we found that affected female GS had mild to moderate hypokalemia and few clinical symptoms. Although the gender differences have been reported in the presentations of familial periodic paralysis (25), pseudohypoaldosteronism type II due to Q565E WNK4 mutation (26), Cushing disease, and other disorders (27), the mechanisms of gender difference on clinical features in Chinese patients with NCC mutations remain to be established. It seems that gender may play an important role in the regulation of NCC, as shown in the animal studies. For example, it has been shown that the density of NCC in the DCT could be influenced by sex hormones (28). In ovariectomized rats, rNCC immunoreactive renal membrane protein is reduced, apical plasma complex location and immunogold label for rNCC in the DCT is decreased, and estradiol replacement restores DCT ultrastructure and rNCC label to normal (29). It is possible that the positive effect of estrogen on NCC may contribute to the less severe findings in females who have GS with NCC mutations. In light of rare gender differences in clinical reports from western countries, the combination of gender and racial difference may account for phenotype manifestation in Chinese patients with GS.

Our study also unveiled some GS patients with hypomagnesemia who had no obvious symptoms. This interesting observation has also been seen in affected family members with profound hypomagnesemia from autosomal dominant isolated renal Mg²⁺ wasting (30). Perhaps psychogenic or environmental factors may modify the severity of the symptoms in GS patients with hypomagnesemia. Alternatively, a background gene could be affecting the clinical symptoms in GS patients with hypomagnesemia.

Renal function is usually normal in patients with GS. However, our male patient 19 had an elevated serum Cr value. This patient also had bilateral renal cysts on renal sonography and typical tubulointerstitial nephritis and renal tubule vacuolization on renal biopsy, all of which have been associated with chronic hypokalemia (31, 32). In rats with chronic hypokalemia, ammoniagenesis is probably stimulated because of the associated intracellular acidosis (33). It has been suggested that a high medullary concentration of NH₄⁺/NH₃ elicits complement activation, initiating the influx of immune cells into the interstitium (34). Because no other causes for his renal insufficiency were identified, we suspect that it might be related to chronic and profound hypokalemia. In support of this speculation, hypokalemic nephropathy can cause end-stage renal disease in patients with long-standing hypokalemia due to eating disorders or laxative abuse (35). Although the long-term prognosis in preserving renal function is believed to be excellent, two patients with GS have been reported to develop end-stage renal failure requiring dialysis (36, 37). To prevent hypokalemia-induced nephropathy, aggressive correction of hypokalemia should be attempted.

Hypocalciuria, a distinct finding used to discriminate the clinical diagnosis of GS from BS, and hypomagnesemia are very common in patients with GS due to NCC mutations. In this study, we found that four patients who did not have hypocalciuria were initially diagnosed as BS. In addition, four patients with either GS or BS did not have hypomagnesemia. NCC and not CLCNKB mutations were identified in all these patients. In fact, normocalciuria and/or normomagnesemia have been reported in some patients with GS due to NCC mutations (38, 39, 40, 41). The reasons of normocalciuria and/or normomagnesemia in patients with NCC mutations remained elusive. Perhaps the persistent and profound hypokalemia may have compromised the function of loop of Henle, a nephron segment that reabsorbs a large portion of filtrated calcium and caused a high distal delivery of calcium exceeding the capacity of the connecting tubule to reabsorb this calcium, leading to normocalciuria or hypercalciuria (9). Ionic channels belonging to the transient receptor potential channel family are claimed to be possible regulators of renal Mg²⁺ reabsorption (42). It was speculated that these or unknown Mg²⁺ regulators may diminish renal Mg²⁺ wasting caused by a NCC mutation and account for the absence of hypomagnesemia in some patients with GS.

Because most patients with GS are compound heterozygotes, and the documentation of independent mutant alleles could be identified within the same kindred, it is reasonable to suggest that mutant alleles should not be rare. In the Swedish and Italian population studied, the prevalence of heterozygous mutations based on phenotypic expression is approximately 1% (31). In a recent study from Japan, gene detection for the nine identified NCC mutations using the TaqMan system in 1852 subjects revealed that the overall frequency of heterozygous NCC mutations was 3.21%, higher than expected, and the estimated number of GS patients was 10.3 among 10,000 subjects (43). Our study also showed that the overall incidence of positive heterogeneous mutations for 12 NCC mutations in 100 unrelated healthy Chinese subjects was approximately 3%. A further large-scale study to detect the NCC mutations is warranted to verify the true prevalence of GS in Chinese populations. Because nine mutations including T60M, H90Y, T163M, 971InsACCGAAAATTTT, R642C, S710stop, R871H, R928C, and R959frameshift were found in at least two unrelated families, it is possible that these mutations are common in Chinese GS patients. Screening of the hot spot NCC mutations may provide an early diagnosis of GS in Chinese families with chronic hypokalemia and metabolic alkalosis.

In conclusion, we have identified 12 NCC mutations in Chinese patients with phenotypic presentation of either GS or BS. We observed that males had severe hypokalemia and paralytic episodes as being the most common presenting symptoms, whereas females had mild to moderate hypokalemia with less serious symptoms. Gender effect may partly explain this phenotype variability. Few patients with NCC mutations did not have typical laboratory signature of hypomagnesium and/or hypocalciuria. Identification of NCC mutations is warranted even in patients with a clinical diagnosis of BS-like syndrome. Screening of hot spot NCC mutations in Chinese populations may provide prenatal and postnatal diagnosis of GS.

	Acknowledgments

 
We thank Dr. Mitchell L. Halperin for his critique of this manuscript.

	Footnotes

 
This work was supported by the National Science Council, Taiwan (Grant NSC 93-2314-B-016-031) and by the Research Fund of Tri-Service General Hospital (Grant TSGH-C-93-51).

First Published Online February 1, 2005

Abbreviations: BS, Bartter’s syndrome; CLCNKB, basolateral chloride channel; Cr, creatinine; DCT, distal convoluted tubule; GS, Gitelman’s syndrome; NCC, NaCl cotransporter; RFLP, restriction fragment length polymorphism; SSCP, single-strand confirmational polymorphism.

Received September 25, 2004.

Accepted January 24, 2005.

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