Regulation of the Renal Na/K/2Cl Cotransporter Gene

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Abstract

The recently cloned bumetanide-sensitive Na/K/2Cl cotransporters (ENCC2-3) and thiazide-sensitive Na/Cl cotransporter (ENCC1) have important roles in sodium chloride absorption and secretion, cell volume regulation, ammonium accumulation in medullary interstitium, and ammonium excretion. Genetic mutations of bumetanide-sensitive Na/K/2Cl cotransporters and thiazide-sensitive Na/Cl cotransporter cause the hereditary hypokalemic alkalosis of some Bartter’s syndrome and Gitelman’s syndrome, respectively. The transporters are sensitive to diuretics and several hormones. Dehydration and acidosis influence the gene expression of ENCC3 but not of ENCC1-2. In contrast, sodium loading increases ENCC2 protein expression in the outer medulla.

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Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

D B Simon, C Nelson-Williams, M J Bia … (1996)

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, 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 chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

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Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

S. Sanjad, Fiona Karet Frankl, Leila Hamdan … (1996)

Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.

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Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 1998

Publication date (Print): August 1998

Publication date (Electronic): 15 July 1998

Volume: 6

Issue: 4

Pages: 272-276

Affiliations

Third Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

Article

Publisher ID: 20532 Other ID: Exp Nephrol 1998;6:272–276

DOI: 10.1159/000020532

SO-VID: 3e34dece-d8de-4c8b-a239-2764ce9309a8

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Regulation of the Renal Na/K/2Cl Cotransporter Gene

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Abstract

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Karger: Nephrology

Most cited references 2

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

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