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Abstract

Mutations in the Na-K-2Cl cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Bartter's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP-sensitive K+ channel that 'recycles' reabsorbed K+ back to the tubule lumen. Examination of the ROMK gene reveals mutations that co-segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.

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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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Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.

E Lander, D Botstein (1987)

An efficient strategy for mapping human genes that cause recessive traits has been devised that uses mapped restriction fragment length polymorphisms (RFLPs) and the DNA of affected children from consanguineous marriages. The method involves detection of the disease locus by virtue of the fact that the adjacent region will preferentially be homozygous by descent in such inbred children. A single affected child of a first-cousin marriage is shown to contain the same total information about linkage as a nuclear family with three affected children. Calculations show that it should be practical to map a recessive disease gene by studying DNA from fewer than a dozen unrelated, affected inbred children, given a complete RFLP linkage map. The method should make it possible to map many recessive diseases for which it is impractical or impossible to collect adequate numbers of families with multiple affected offspring.

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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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PubMed ID:: 8841184

DOI:: 10.1038/ng1096-152

ScienceOpen disciplines: Chemistry

Keywords: Amino Acid Sequence,Bartter Syndrome,genetics,Carrier Proteins,Cell Membrane,chemistry,Consanguinity,Conserved Sequence,DNA Mutational Analysis,Female,Genetic Heterogeneity,Genotype,Humans,Male,Mutation,Pedigree,Polymorphism, Single-Stranded Conformational,Potassium Channels,Potassium Channels, Inwardly Rectifying,Sodium-Potassium-Chloride Symporters

Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.

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Most cited references 11

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

Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.

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

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