Identification of a novel R642C mutation in Na/Cl cotransporter with Gitelman's syndrome.

Gitelman's syndrome, a variant of Bartter's syndrome, is an inherited disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, and these abnormalities have recently been linked to the thiazide-sensitive Na/Cl cotransporter (TSC) gene. We evaluated three unrelated patients affected with this syndrome whose diagnosis was made based on clinical and biochemical features. The data of clearance studies in these patients were compatible with Gitelman's syndrome. We then investigated possible mutations of the TSC gene. In one patient whose parents are consanguineous, we identified a novel missense mutation in the TSC gene, which causes alteration of arginine to cysteine at codon 642 (R642C mutation) located in the cytoplasmic tail of the product. This mutation results in the loss of an MspI site in exon 15 of the TSC gene. MspI digestion analysis of genomic DNA fragments from the family was consistent with the autosomal recessive inheritance of the disorder, and presence of this mutation correlated with the clinical manifestations. Such mutation was not detected in 47 normal healthy subjects. In the second patient, we found another missense mutation in one allele of the TSC gene, which results in alteration of arginine to glutamine at codon 955. In the third patient, no mutation causing amino acid substitution was found in the TSC gene. These results indicate that the R642C mutation in TSC is critically important for impairment of this cotransporter function and also suggest the necessity of further investigations in the genetic background of Gitelman's syndrome.