A High Prevalence of Gitelman's Syndrome Mutations in Japanese

Abstract

Although Gitelman's syndrome (GS) is considered a rare disorder, it is an autosomal recessive phenotype and the frequency of heterozygote subjects might be higher than suspected. The purpose of this study was to assess the prevalence of GS in Japanese and the effects of heterozygous GS mutations on blood pressure levels. We used the TaqMan system to detect 9 Gitelman's syndrome mutations in SLC12A3 that have been reported in Japanese. We then conducted association studies between these mutations and blood pressure in 1,852 subjects recruited from the Suita study, representing the general population in Japan.Among these 1,852 subjects, we detected the T180K, A569V, L623P, R642C, and L849H heterozygote genotypes in 56, 14, 1, 1, and 47 subjects, respectively. The overall frequency of GS mutations was (56 14 1 1 47) / (1,852 2) 0.0321, which was much higher than suspected. This means we should expect to find one subject with a heterozygous GS mutation among 15.6 Japanese or that we should find 10.3 GS subjects among 10,000 Japanese. Although the blood pressure levels of subjects heterozygous for the T180K, A569V, or L849H genotype were not significantly different from those of wild-type subjects, urine pH in subjects with GS mutations was significantly higher than that in subjects without mutations. In conclusion, GS could be one of the major causes of low blood pressure in Japanese. (Hypertens Res 2004; 27: 327-331)

Functional Confirmation of Gitelman's Syndrome Mutations in Japanese

“…We found 56 subjects heterozygous with the 180K allele, 14 subjects heterozygous with the 569V allele, 1 subject with the 623P allele, 1 subject with the 642C allele, 47 subjects with the 849H allele, and 1 compound heterozygous subject with the 180K and 849H alleles, in total of 1,852 subjects (3). Thus, the combined allele frequency of the GS mutations was 0.0321.…”

“…However, almost all of the reported GS mutations were from case reports without functional confirmation (2,3). It is possible that the reported mutations were simply polymorphisms and the true mutations were in linkage with the polymorphisms in the reported pedigree.…”

Loss of Consciousness and Hypokalemia in an Elderly Man with a Mutation of the Thiazide-sensitive Na-Cl Cotransporter Gene

“…All three of these cases showed mild hypokalemia and a case reported by Monkawa et al showed mild hypocalciuria, as seen in the present study. Tago et al recently reported the prevalence of mutations of the TSC gene in Japanese and found that the frequency of GS mutations was 0.0321 [23]. The frequency of mutations causing 180K, 569V and 849V were 1.51, 0.38 and 1.27%, respectively.…”

A pedigree analysis of two homozygous mutant Gitelman syndrome cases

“…In the test of SLC12A3 gene mutation of GS patients, negative genetic testing could involve large genomic rearrangements that are missed by direct sequencing that usually accounts for 6% of mutations [17]. Reports have indicated that the heterozygous mutations frequency of European and Asian is about 3% and 1% respectively, the morbidity is 1/1000-9/10000 [18,19]. Although the GS patients who have been confirmed by gene mutation are constantly increasing, up to 40% of GS patients carry only a single mutation in SLC12A3 instead of being compound heterozygous or homozygous [17].…”