title: Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension.
abstract: The chloride channel ClC-Kb is expressed in the basolateral cell membrane of the distal nephron and participates in renal NaCl reabsorption. Loss-of-function mutations of ClC-Kb lead to classic Bartter syndrome, a rare salt-wasting disorder. Recently, we identified the ClC-Kb(T481S) polymorphism, which confers a strong gain-of-function effect on the ClC-Kb chloride channel. The present study has been performed to explore the prevalence of the mutation and its functional significance in renal salt handling and blood pressure regulation. As evident from electrophysiological analysis with the 2-electrode voltage-clamp technique, heterologous expression of ClC-Kb(T481S) in Xenopus oocytes gave rise to a current that was 7-fold larger than the current produced by wild-type ClC-Kb. The prevalence of the mutant allele was significantly higher in an African population from Ghana (22%) than in whites (12%). As tested in 1 white population, carriers of ClC-Kb(T481S) were associated with significantly higher systolic (by approximately 6.0 mm Hg) and diastolic (by approximately 4.2 mm Hg) blood pressures and significantly higher prevalence (45% versus 25%) of hypertensive (> or =140/90 mm Hg) blood pressure levels. Individuals carrying ClC-Kb(T481S) had significantly higher plasma Na+ concentrations and significantly decreased glomerular filtration rate. In conclusion, the mutation ClC-Kb(T481S) of the renal epithelial Cl- channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo.
authors.affiliation: Department of Pediatrics, University of Marburg, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Jeck
authors.forename: Siegfried
authors.initials: S
authors.lastname: Waldegger
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Christoph
authors.initials: C
authors.lastname: Boehmer
authors.forename: Petra
authors.initials: P
authors.lastname: Waldegger
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrich
authors.forename: Teut
authors.initials: T
authors.lastname: Risler
authors.forename: Robert
authors.initials: R
authors.lastname: Moehle
authors.forename: Undine E
authors.initials: UE
authors.lastname: Lang
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.forename: Brigitta
authors.initials: B
authors.lastname: Bondy
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Stephen
authors.initials: S
authors.lastname: Asante-Poku
authors.forename: Hannsjörg
authors.initials: H
authors.lastname: Seyberth
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D044383:Black People / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D005869:Ghana; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D017136:Ion Transport / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009318:Natriuresis / Q000235:genetics; D009399:Nephrons / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D011188:Potassium / Q000378:metabolism; D018075:RNA, Complementary / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D044465:White People / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D027321:Anion Transport Proteins; C440005:BSND protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D018075:RNA, Complementary; D012964:Sodium; D011188:Potassium