title: Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.
abstract: Analysis of patients with inherited hypokalaemic alkalosis resulting from salt-wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood-pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss-of-function mutations that impair renal chloride reabsorption in the thick ascending limb of Henle's loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt-wasting, low blood pressure, normal magnesium and hyper- or normocalciuria; they define a distinct subset of patients with Bartter's syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood-pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Simon
authors.forename: R S
authors.initials: RS
authors.lastname: Bindra
authors.forename: T A
authors.initials: TA
authors.lastname: Mansfield
authors.forename: C
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: E
authors.initials: E
authors.lastname: Mendonca
authors.forename: R
authors.initials: R
authors.lastname: Stone
authors.forename: S
authors.initials: S
authors.lastname: Schurman
authors.forename: A
authors.initials: A
authors.lastname: Nayir
authors.forename: H
authors.initials: H
authors.lastname: Alpay
authors.forename: A
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Soriano
authors.forename: J M
authors.initials: JM
authors.lastname: Morales
authors.forename: S A
authors.initials: SA
authors.lastname: Sanjad
authors.forename: C M
authors.initials: CM
authors.lastname: Taylor
authors.forename: D
authors.initials: D
authors.lastname: Pilz
authors.forename: A
authors.initials: A
authors.lastname: Brem
authors.forename: H
authors.initials: H
authors.lastname: Trachtman
authors.forename: W
authors.initials: W
authors.lastname: Griswold
authors.forename: G A
authors.initials: GA
authors.lastname: Richard
authors.forename: E
authors.initials: E
authors.lastname: John
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D001477:Bartter Syndrome / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003434:Crossing Over, Genetic; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007438:Introns; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D018118:Chloride Channels; D017931:DNA Primers