LINKAGE OF GITELMAN-SYNDROME TO THE THIAZIDE-SENSITIVE SODIUM-CHLORIDE COTRANSPORTER GENE WITH IDENTIFICATION OF MUTATIONS IN DUTCH FAMILIES

Gitelman syndrome is a mostly autosomal recessive disorder affecting t he renal tubular function associated with hypokalemia and hypomagnesem ia. Functional studies point to a defect in the distal renal tubule in the thiazide-sensitive, electroneutral sodium-chloride cotransporter (TSC). Based upon the localization of a 2.6 cDNA encoding the human TS C to chromosome 16q13, polymorphic markers spanning the region from 16 p12 to 16q21 were tested for linkage to the Gitelman syndrome locus in three Dutch families with autosomal recessive inheritance of this dis order. Using two-point linkage analysis, a maximum LOD score (Z(max) o f 4.49 (at Theta = 0.00) was found for the marker D16S408. One crucial recombination event places the Gitelman syndrome locus distal to D16S 419 at 16q12-13, Subsequently we have tested our group of Gitelman pat ients for mutations in the human TSC gene. Two mutations were identifi ed in three Gitelman families. Our study confirms that the human TSC g ene is involved in Gitelman syndrome. Patients from three Gitelman fam ilies reveal two identical human TSC mutations, suggesting these famil ies share a common ancestor.