GITELMANS-SYNDROME (BARTTERS VARIANT) MAPS TO THE THIAZIDE-SENSITIVE COTRANSPORTER GENE LOCUS ON CHROMOSOME 16Q13 IN A LARGE KINDRED

A defect in distal renal tubular sodium chloride handling is thought t o be responsible for the clinical phenotype of Gitelman's syndrome, a variant of Bartter's syndrome. To study the possible involvement of th e renal thiazide-sensitive NaCl cotransporter gene in the syndrome, a linkage analysis study in the largest reported kindred with the syndro me was performed, A human homolog of rat thiazide-sensitive cotranspor ter was cloned and mapped to chromosome 16q13 by fluorescent in situ h ybridization. All 17 family members in two generations were genotyped at loci in this region, There were no recombinants observed between th e Gitelman's syndrome phenotype and inheritance of D16S408 alleles, yi elding a lod score of 3.88 at Q = 0. By contrast, recombinants were ob served between Gitelman's syndrome and the flanking markers D16S419 an d D16S400, localizing the responsible gene in this family to a 15 cent imorgan region on chromosome 16q. These genetic data, together with cu rrent understanding of the molecular physiology of the thiazide-sensit ive cotransporter, are strong evidence that the latter is defective in this kindred with Gitelman's syndrome.