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(Hypertension. 2000;36:389.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension

Olle Melander; Marju Orho-Melander; Kristina Bengtsson; Ulf Lindblad; Lennart Råstam; Leif Groop; U. Lennart Hulthén

From the Department of Endocrinology (O.M., M.O.M., L.G., U.L.H.) and the Department of Community Medicine (K.B., U.L., L.R.), Lund University, Malmö, Sweden.

Correspondence to Olle Melander, MD, Department of Endocrinology, Malmö University Hospital MAS, S-205 02 Malmö, Sweden. E-mail Olle.Melander{at}endo.mas.lu.se

Abstract—Gitelman’s syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazide-sensitive 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-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, 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 C1420T variants, found in the mutation screening of subjects without Gitelman’s syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; P=0.03). In conclusion, we confirm that Gitelman’s syndrome 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.

Key Words: DNA • genes • sodium channels • hypertension, genetic

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