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

Melander, Olle LU ; Orho-Melander, Marju LU ; Bengtsson Boström, Kristina LU ; Lindblad, Ulf LU ; Råstam, Lennart LU ; Groop, Leif LU and Hulthén, Lennart LU (2000) In Hypertension 36(3). p.389-394
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Hypertension
volume
36
issue
3
pages
389 - 394
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:10988270
ISSN
1524-4563
language
English
LU publication?
yes
id
606fd1c8-65b9-44fc-a389-43ba0f830b89 (old id 1118057)
alternative location
http://hyper.ahajournals.org/cgi/content/abstract/36/3/389
date added to LUP
2008-06-24 14:01:11
date last changed
2016-04-15 19:48:14
@article{606fd1c8-65b9-44fc-a389-43ba0f830b89,
  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.},
  author       = {Melander, Olle and Orho-Melander, Marju and Bengtsson Boström, Kristina and Lindblad, Ulf and Råstam, Lennart and Groop, Leif and Hulthén, Lennart},
  issn         = {1524-4563},
  language     = {eng},
  number       = {3},
  pages        = {389--394},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Hypertension},
  title        = {Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension},
  volume       = {36},
  year         = {2000},
}