The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes.
Hypokalemic alkalosis with low blood pressure can be caused by a number of medications or alternatively as an autosomal recessive genetic trait. Molecular genetic approaches to this problem have recently demonstrated that mutations in genes encoding the thiazide-sensitive Na-Cl cotransporter or the bumetanide-sensitive Na-K-2Cl cotransporter produce two distinctive clinical and physiological pictures featuring hypokalemic alkalosis. Mutations in the latter cause a phenotypic picture called Bartter's syndrome that includes marked hypercalciuria and neonatal presentation with marked intravascular volume depletion. Mutations in the former cotransporter result in Gitelman's syndrome, which includes hypocalciuria, hypomagnesemia, and typically older clinical presentation with predominant muscular signs and symptoms. These findings establish the molecular basis of these disorders and indicate that the diverse abnormalities seen in affected patients derive from primary defects in these mediators of cotransport function. Moreover, these findings have implications for normal mechanisms of renal electrolyte homeostasis and for potential phenotypic effects in the more common heterozygous carriers of these mutations.
Simon
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Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Lifton
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RP
D000471:Alkalosis / Q000235:genetics*; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D005796:Genes; D008040:Genetic Linkage; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D009154:Mutation; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; D013577:Syndrome
D002352:Carrier Proteins; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters