Clinical significance of thiazide-sensitive Na-Cl cotransporter gene by mutational analysis

Thiazide-sensitive Na-Cl cotransporter (TSC, SLC12A3) is located on chromosome 16q13 and is expressed specifically in the renal distal convoluted tubule, where it mediates the reabsorption of Na+ and Cl-. Mutation of TSC is known to be responsible for Gitelman's syndrome, an autosomal recessive renal tubular disorder characterized by low blood pressure due to renal sodium wasting, hypokalemia, metabolic alkalosis, hypomagnesemia and normocalcemic hypocaliuria. We assessed mutational analysis of the TSC gene in 35 patients with Gitelman's syndrome. We found 16 missense mutaions, insertion of 18bp in the 6th exon, deletion of C in the 9th exon and deletion of C in the 16th exon. These results suggest that there is no mutational hot spot in the TSC gene. These 19 mutations include eight novel mutations: R261C, N406H, A523T, M672I, R1009Q, N1014K, deletion of C in the 9th exon and deletion of C in the 16th exon. The eight novel mutations might be responsible for impairment of NaCl reabsorption leading to the principal clinical features of Gitelman's syndrome in these patients. These mutations could bring new insights into genotype-phenotype correlations among the hypokalemic tubulopathies. Recently, genome-wide association studies, using SNPs to identify loci involved in susceptibility to common diseases, showed that the TSC gene may contribute to genetic susceptibility to diabetic nephropathy in Japanese. In addition, substitution of Arg904 to Gln in the TSC gene has been reported to predispose essential hypertension in Swedish and Japanese populations. Further studies are needed to clarify the possible associations of the TSC gene with common diseases.