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NDT Advance Access published online on November 25, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn619
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Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure

Yu-Juei Hsu1, Sung-Sen Yang1,2, Nain-Feng Chu3, Huey-Kang Sytwu2, Chih-Jen Cheng1 and Shih-Hua Lin1,2

1 Division of Nephrology, Department of Medicine, Tri-Service General Hospital 2 Graduate Institute of Medical Sciences 3 Department of Community Medicine, Tri-Service General Hospital and School of Public Health, National Defense Medical Center, Taipei, Taiwan

Correspondence and offprint requests to: Shih-Hua Lin, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Tel: +886-2-87927213; Fax: +886-2-87927134; E-mail: shihhualin{at}yahoo.com



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Gitelman's syndrome (GS), which is caused by homozygous or compound heterozygous mutations of the thiazide-sensitive sodium chloride cotransporter (NCC), usually manifests in children and is associated with low blood pressure. However, the prevalence of heterozygous NCC mutations and their association with blood pressure in children have not yet been studied.

Methods. Five hundred unrelated children from the Taipei Children Heart Study were enrolled. Genomic DNA was isolated from peripheral blood and the SLC12A3 gene was amplified by polymerase chain reaction (PCR). The 15 NCC mutations previously identified in Chinese patients with GS were evaluated using restriction fragment length polymorphism (RFLP) analysis. Blood pressure, biochemistry and urine pH were measured. The allelic frequency of heterozygous NCC mutations and their association with low blood pressure were also investigated.

Results. RFLP analysis for the 15 NCC mutations revealed heterozygous T60M in 1 child, T163M in 1, S283Y in 4, R642C in 2, W844X in 2, R928C in 9 and R959frameshift in 10 children. The overall incidence of positive heterozygous NCC mutations was ~2.9%. There were no significant differences in systolic or diastolic blood pressure, biochemical profiles or urine pH between children with heterozygous NCC mutations (n = 29) and non-affected controls (n = 471), except for slightly higher fasting plasma glucose concentrations in NCC-heterozygous children (91 ± 2.3 versus 88 ± 0.4 mg/dL, P < 0.05). Examination among the different NCC mutations showed that these children also had comparable blood pressures.

Conclusions. We found a relatively high prevalence of heterozygous NCC mutations in Chinese children, suggesting that GS may not be rare in this population. Heterozygous NCC mutations were not associated with lower blood pressure in these Chinese children.

Keywords: allelic frequency; blood pressure; Gitelman's syndrome; heterozygous mutation; sodium chloride cotransporter (NCC)



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Gitelman's syndrome (GS) (OMIM 263800 [OMIM] ) is an autosomal recessive salt-losing tubulopathy characterized by hypokalaemic alkalosis with hypomagnesaemia and hypocalciuria [1,2]. Due to similarities with chronic thiazide administration in laboratory studies, GS was long considered to be a functional defect of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubules (DCT) [3,4]. Using a candidate gene approach, Simon et al. [3] were the first to identify inactivating mutations in the SLC12A3 gene encoding NCC from families of GS patients in 1996. To date, more than 100 distinct NCC mutations have been identified in patients with GS [5,6]. The majority of patients are compound heterozygotes having two different mutations on the two alleles for NCC [3,7]. Furthermore, it has been reported that 7% of GS patients carried three or more different NCC mutations [8]. Multiple independent mutant alleles have also been found in families having GS [8,9]. Given these findings, we predict that heterozygous NCC mutations should not be rare in general populations. Therefore, elucidating the prevalence of heterozygous NCC mutations will help to estimate the incidence of GS and will aid in understanding the physiologic effects of heterozygous NCC.

Patients with GS usually present with clinical symptoms during childhood or adolescence that include low blood pressure due to renal salt wasting [10,11]. In a large Amish kindred with GS, patients with homozygous NCC actually had impaired renal sodium (Na+) reabsorption and significantly lower blood pressure than their non-affected relatives [10]. Children, but not adults, with heterozygous NCC mutations also had significantly lower blood pressure and higher 24-h urine Na+ excretion than non-affected controls. Nevertheless, there is still a lack of large epidemiologic studies that have examined correlations between heterozygous NCC mutations and blood pressure in children. To date, we have identified 15 NCC mutations that include 11 missense, 2 nonsense, 1 insertion and 1 deletion mutations in Chinese patients with GS [12,13]. Most of these NCC mutations were recurrent and were relatively different from those reported in Western countries (Table 1) [14]. These 15 NCC mutations were selected as candidates for heterozygous NCC mutations. Therefore, the aims of this study were to investigate the allele frequency of these 15 heterozygous NCC mutations in 500 Chinese children, to estimate the prevalence of GS and to assess its association with blood pressure.


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  		Table 1 NCC mutations, enzyme restriction and allele frequency in Chinese children

 


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Subjects
This study is a part of the Taipei Children Heart Study, an epidemiologic cohort designed to evaluate risk factors for cardiovascular disease (CVD) among school children in Taipei in 1995. The sampling methods and results have been clearly described elsewhere [15]. The genotypes of NCC mutations were determined in 500 children having a mean age of 13.3 years (range 12–16 years). The study protocol was approved by the Ethics Committee on Human Studies at Tri-Service General Hospital, National Defense Medical Center in Taiwan, ROC. Informed consent was obtained from all study parents and children.

Blood pressure and biochemical profiles
Blood pressure was measured after a 10-min rest period in a sitting position. Systolic and diastolic pressures were calculated from the mean of two measurements by well-trained doctors using mercury sphygmomanometers. Twelve-hour fasting blood samples were obtained and biochemical values, including creatinine, blood urea nitrogen, lipid profiles, liver profiles and uric acid, were determined by automated methods (AU 5000 chemistry analyser; Olympus, Tokyo, Japan). First morning-voided urine after overnight fast was collected and urine pH was measured with a pH electrode.

Genomic DNA isolation and polymerase chain reactions (PCR)
Genomic DNA was isolated from peripheral blood for PCR amplification of individual exons of the SLC12A3 gene [National Center for Biotechnology Information (NCBI) number NM-000339].

Restriction fragment length polymorphism analysis (RFLP)
Fifteen NCC mutations including 12 previously reported and 3 newly identified mutations in Chinese patients with GS were selected (Figure 1) [12,13]. PCR-amplified DNA fragments were digested with 15 different restriction enzymes (Table 1), and electrophoresis was carried out on a 2% agarose gel. The detection of NCC mutations by RFLP was confirmed by direct sequencing.


Figure 1
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  		Fig. 1 Schematic diagram of 15 NCC mutations in Chinese GS patients. The NCC is represented as a 12-transmembrane domain protein with cytoplasmic amino and carboxyl termini. The sites of mutations in exons are denoted by arrows.

 
Allele frequency of mutated NCC
RFLP analysis was used to count the occurrence of the 15 above-mentioned mutations (a = the number of occurrences of the first mutation in the sample population, b = occurrences of the second mutation, etc.). The overall incidence of positive heterozygous mutations was calculated as (a + b + c + d + e + ...)/(500 x 2).

Statistical analysis
The data are expressed as means ± SEM. Student's unpaired t-tests were used to compare differences in clinical and biochemistry characteristics between the group of children with all the heterozygous NCC mutations and those with wild-type NCC. Analysis of covariance (ANCOVA) was used to compare differences in continuous variables among the seven different NCC subgroups after adjustment for age and sex. The Bonferroni multiple comparisons procedure was used for multiple pairwise comparisons between the subgroups. The Kruskal–Wallis test was used when the variables among these groups were not normally distributed. Differences were considered significant when the P value was <0.05.



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Allele frequency of NCC mutations
Among the 500 children, RFLP analysis for the 15 NCC mutations revealed heterozygous T60M in 1 child, T163M in 1, S283Y in 4, R642C in 2, W844X in 2, R928C in 9 and R959frameshift in 10 children (Table 1). Among these NCC mutated alleles, the R928C and R959frameshift alleles were the most common in this population of Chinese children. The H90Y, L215P, IVS7-1G>A+971InsACCGAAAATTTT, N426K, N442K, T649M, S710stop and R871H mutations were not detected at all. The frequencies of the T60M, T163M, S283Y, R642C, W844X, R928C and R959frameshift alleles were 0.1, 0.1, 0.4, 0.2, 0.2, 0.9 and 1.0 %, respectively. The overall incidence of positive heterozygous NCC mutations was ~2.9%.

Blood pressure and biochemistry in non-affected and NCC-heterozygous children
As shown in Table 2, blood pressure was similar in children with heterozygous NCC mutations (systolic 114 ± 2.9, diastolic 67 ± 1.7 mmHg; n = 29) and in non-affected controls (systolic 116 ± 0.7, diastolic 68 ± 0.9 mmHg; n = 471). Notably, we found that NCC-heterozygous children had slightly but significantly higher fasting plasma glucose concentrations compared to non-affected controls after adjusting for age, sex and body mass index (BMI). However, there were no differences in plasma creatinine, blood urea nitrogen, lipid profiles, liver profiles or uric acid between non-affected and NCC-heterozygous children. Urine pH was also comparable between non-affected and NCC-heterozygous children (urine pH 5.7 ± 0.03 versus 5.7 ± 0.14).


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  		Table 2 Blood pressure and biochemistry in NCC-heterozygous children

 
Blood pressure and biochemistry in children with different NCC-heterozygous mutations
Clinical and biochemical parameters of children carrying seven observed NCC-heterozygous mutations are shown in Table 3. There was no significant difference in blood pressure among these seven subgroups. Although systolic blood pressure in children heterozygous for the R959frameshift was lower than that in children with other NCC heterozygotes, this difference did not reach statistical significance after adjusting for age and gender. In addition, both systolic and diastolic blood pressures in children heterozygous for R959frameshift were comparable with age- and gender-matched non-affected controls.


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  		Table 3 Blood pressure and biochemistry in NCC-heterozygous children

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we examined the prevalence of heterozygous NCC mutations as well as associations between these mutations and blood pressure in 500 Chinese children. We found that the allelic frequency of heterozygous NCC mutations was higher than expected at ~2.9%. Overall, NCC-heterozygous children did not have lower blood pressures but did have significantly higher fasting plasma glucose levels than non-affected controls.

Only a few studies have addressed the prevalence of heterozygous NCC mutations in large general populations [13,16–18]. In Western countries such as Sweden and Italy, the prevalence of heterozygous mutations, based on phenotypic expression, has been estimated at ~1%. However, the carrier prevalence of the 15 NCC mutations in the Framingham Heart Study, which were proven or inferred to be functional from the screen of entire coding exons in 3125 unrelated subjects, was ~0.5% [19]. In the Far East, the overall frequency of nine heterozygous NCC mutations, as detected by the TaqMan system, was 2.0% in 1852 Japanese subjects [16,20]. Using RFLP, our previous study showed that the heterozygous carrier rate for 12 previously identified NCC mutations in 100 unrelated healthy Chinese adults was ~3% [13]. In the current study, the allele frequency of 15 heterozygous NCC mutations in 500 Chinese children was similar at ~2.9%. A recent study in China also found a 3% prevalence of heterozygous NCC mutations using direct sequencing screening for 10 NCC mutations in 50 unrelated healthy subjects [21]. This discrepancy in the prevalence of heterozygous carriers between Western and Asian countries may be explained by the screening methods used to detect the entire NCC gene or selected NCC variants or by the pathogenicity of selected NCC mutations. If the pre-selected 15 NCC mutations in our study were all pathogenic, the expected prevalence of patients with autosomal recessive GS would be at least 2.1 per 10 000 children (2.9/100 x 2.9/100 x 1/4). Our results suggest that GS should not be rare in Chinese populations and is more common than in Western countries. Because most patients with GS may have non-specific symptoms such as weakness, fatigue, cramps, nocturia, thirst and salt craving during early childhood, which significantly impacts quality of life [2,5,22], an early diagnosis is often difficult but needed. Screening for recurrent ‘hot spot’ NCC mutations in children and in suspected patients may enhance genetic counselling for heterozygous carriers and provide earlier diagnosis of GS.

NCC is a member of the cation/Cl– cotransporter gene family. The NCC mutations in GS are located throughout the entire coding sequence of the NCC protein [5,12,13,23]. Most of the reported NCC mutations reside in the carboxyl terminus, which is involved in the intracellular trafficking of NCC to the apical membrane [13,24–26]. In the present study, four out of seven (57%) heterozygous NCC mutations were located within the cytoplasmic carboxyl terminus, and we found that R928C (0.9%) and R959frameshift (1.0%) were the two most common heterozygous NCC mutations among Chinese children. As expected, a frameshift of NCC from R959 causes protein dysfunction and should be pathogenic [9]. R928C has also been proposed to be pathogenic since R928 is conserved among various species and because substitution of arginine (R) to cysteine (C), which introduces a sulphur-containing side chain or removes a cationic amino acid, may result in a functional defect of NCC. R928C has not been reported as a polymorphism in other ethnic groups. Nevertheless, an in vitro functional expression study of R928C will be needed to confirm the pathogenicity of this mutant by measuring tracer 22Na+ uptake in oocytes or mammalian cells.

NCC activity in the DCT has been implicated in the regulation of blood pressure. In contrast to the enhanced NaCl reabsorption in the DCT seen in pseudohypoaldosteronism type II due to WNK1/4 mutations with secondary hypervolaemia and hypertension [27], diminished renal NaCl reabsorption due to NCC mutations in GS causes renal salt wasting and relative hypovolaemia leading to low or normal blood pressure [10,11]. It has been proposed that heterozygous NCC carriers may also have impaired renal salt reabsorption and increased susceptibility to diuretics. A previous study in a large Amish family having GS demonstrated that heterozygous children, but not adults, had significantly lower blood pressure accompanied by higher urinary Na+ excretion than their non-affected relatives [10]. Why this phenomenon was seen only in children remains elusive. However, an additional intra-familial study in Sweden found that NCC-heterozygous subjects had significantly lower blood pressures but did not have higher urinary Na+ excretions than controls [11]. A new study by Ji et al. [19] showed that the inactivating NCC carrier was associated with a significant reduction in blood pressure and a reduced risk of hypertension in a Western population [19]. Conversely, the NCC-heterozygous children in our study and NCC-heterozygous adults in a Japanese study did not have a relative hypotension [28]. This discrepancy may be explained by racial differences, genetic background or variable salt intakes in these studies.

The nature and position of NCC mutations may be a determining factor in the severity of GS. Among the different NCC mutations in this study, children carrying the R959frameshift, T60M and T163M mutations appeared to have lower blood pressures than the other NCC heterozygotes. However, this difference did not reach statistical significance after adjusting for age and gender. The number of individuals with specific NCC mutations was very limited. Therefore, a larger cohort will be needed to clarify whether blood pressure is related to specific heterozygous NCC mutations.

We found that NCC-heterozygous children had slightly higher fasting plasma glucose concentrations than non-affected controls. This finding is in line with a Swedish study that examined relatives of families having GS, which also showed significantly higher fasting glucose in NCC-heterozygous relatives [11]. Although it is not known whether glucose metabolism and insulin resistance are altered in GS patients, glucose intolerance has been shown in patients treated with thiazide diuretics. Diuretic-related hypokalaemia and activation of renin–angiotensin–aldosterone have been suggested as causes of impaired glucose tolerance in thiazide-treated patients [29–31]. However, normal serum potassium concentrations and a lack of correlation between plasma glucose, renin and aldosterone levels in NCC-heterozygous relatives in the Swedish study argue against a diuretic-like mechanism. Because NCC expression has not been examined in the insulin-secreting pancreas or insulin-sensitive tissue such as skeletal muscle, liver and adipose, the role of heterozygous NCC mutations in glucose metabolism merits further investigation.

There are some limitations to the present study. Firstly, it is well known that some dietary factors, such as reduced salt intake and increased potassium intake, can effectively lower blood pressure levels [32]. However, all the children in this study continued with their usual diet without any restriction in salt or potassium. Secondly, we did not measure urinary excretion of Na+ or other electrolytes and could not evaluate possible correlations with blood pressure. However, Fava et al. [11] did not find any correlation between blood pressure and urine Na+ excretion in NCC-heterozygous and non-affected subjects. Thirdly, the number of children carrying different individual heterozygous NCC mutations was relatively small. It was therefore difficult to determine effects of different specific heterozygous NCC mutants on blood pressure. Fourthly, we sequenced only fragments of NCC mutations detected by RFLP rather than the entire SLC12A3 gene. Finally, this study was observational and cross-sectional in design. Further larger scale longitudinal studies as well as additional in vitro and in vivo benchwork are needed to examine the effects of heterozygous NCC on blood pressure and glucose metabolism.

In conclusion, we found a relatively high prevalence of heterozygous NCC mutations in Chinese children, suggesting that the GS prevalence may not be rare in this population. NCC-heterozygous children did not have significantly lower blood pressure but did have higher fasting plasma glucose concentrations. The possibility that heterozygous NCC mutations affect the cardiovascular system and glucose metabolism warrants further investigation.



   Acknowledgments
 
This study was supported in part by a grant from the National Science Council, Taiwan (NSC 96-2314-B-016-037), the Research Fund of Tri-Service General Hospital (TSGH-C-95-47 and -96-53), and Chen-Han Foundation for Education. We are much indebted to Dr Mitchell L. Halperin for his critique of this manuscript.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 4. 7.08
Accepted in revised form: 10.10.08


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