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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 approximately 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.

Mutations in the thiazide-sensitive Na-Cl cotransporter (SLC12A3) are considered to cause Gitelman's syndrome (GS), an autosomal recessive inherited renal tubular disorder. In the present study, to assess the prevalence of 3 SLC12A3 missense mutations(T180K, L849H, and R919C), involving community-based subjects with hypokalemia, mutation analysis was performed in 1567 subjects in Aomori Prefecture, a northern part of Japan. All subjects were participants in the Iwaki Health Promotion Project. Genotypes of the SLC12A3 mutations were determined by the TaqMan PCR method. Among these 1567 subjects, we detected missense mutations of T180K, L849H, and R919C in 40, 49, and 57 subjects, respectively. One subject had a homozygous (L849H) and heterozygous (R919C) mutation. Two subjects had homozygous mutations (R919C). Five subjects had compound heterozygous mutations: 2 subjects with T180K and R919C, one subject with T180K and R919C, and 2 subjects with L849H and R919C. One hundred and thirty-two subjects had a heterozygous mutation, and 1427 subjects had no mutations. The overall frequency of GS mutations was 8.9%. The mutant allele frequency of T180K, L849H, and R919C was 1.3, 1.6, and 1.9%, respectively. The GS mutant allele frequency of the 1,567 Japanese was more than 4.8%. The present study revealed that the allele frequency of these GS mutations was 4.8% in a Japanese population. In addition, these findings suggest that the allele frequency of GS mutations may be higher than expected, although GS is considered to be a rare disorder.

Background: Inactivating mutations of the SLC12A3 gene are the most common cause of Gitelman's syndrome (GS), a disorder inherited as an autosomal recessive trait. In a minority of cases, GS-like phenotypes are caused by mutations in the CLCNKB gene., Methods: We searched for SLC12A3 and CLCNKB gene mutations in 13 Chinese patients (9 males and 4 females, age 35 +/- 14 years) from 8 unrelated families with the clinical and biochemical features of GS. All coding regions, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis., Results: We identified 10 mutations distributed throughout the SLC12A3 gene. Seven are novel variants, including 4 missense mutations (Gly196Val, Cys430Gly, Gly439Val and Leu571Pro), 2 deletions (1384delG and 346-353delACTGATGG) and 1 in-frame insertion (997insCys). Three mutations were recurrent, including 2 missense mutations (Thr60Met and Asp486Asn) and 1 deletion (2883-2884delAG). The homozygous or heterozygous mutation Thr60Met was found in 8 of 13 patients. There were no mutations detected in the CLCNKB gene., Conclusions: Thr60Met may be the most common mutation in Chinese patients with GS. Possible specific genotype-phenotype correlations were difficult to identify., (Copyright 2008 S. Karger AG, Basel.)