Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension

Gitelman's syndrome is an autosomal recessive disorder characterized by ele ctrolyte disturbances and low blood pressure. The disease is caused by homo zygous or compound heterozygous inactivating mutations in the thiazide-sens itive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensiti ve NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hyp othesized that such mutations in their heterozygous form protect against pr imary hypertension in the general population and that the gene may also har bor activating mutations that increase the risk for primary hypertension. A ccordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C142 0T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were deter mined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overre presented in hypertensive patients compared with normotensive subjects (5 o f 292 versus 0 of 264; P=0.03). In conclusion, we confirm that Gitelman's s yndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension.