GITELMANS VARIANT OF BARTTERS-SYNDROME, INHERITED HYPOKALEMIC ALKALOSIS, IS CAUSED BY MUTATIONS IN THE THIAZIDE-SENSITIVE NA-CL COTRANSPORTER

Maintenance of fluid and electrolyte homeostasis is critical for norma l neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeost asis including hypokalaemic metabolic alkalosis; Gitelman's syndrome r epresents the predominant subset of Bartter's patients having hypomagn esemia and hypocalciuria. We now demonstrate complete linkage of Gitel man's syndrome to the locus encoding the renal thiazide-sensitive Na-C l cotransporter, and identify a wide variety of non-conservative mutat ions, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chlorid e reabsorption in the more common heterozygotes, potentially protectin g against development of hypertension.