title: KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.
abstract: Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche Scientifique (UMRS) 970, Paris-Centre de Recherche Cardiovasculaire (PARCC), Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Louis-Dit-Picard
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.forename: Daniel
authors.initials: D
authors.lastname: Trujillano
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Miserey-Lenkei
authors.forename: Nabila
authors.initials: N
authors.lastname: Bouatia-Naji
authors.forename: Olena
authors.initials: O
authors.lastname: Pylypenko
authors.forename: Geneviève
authors.initials: G
authors.lastname: Beaurain
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Olivier
authors.initials: O
authors.lastname: Sand
authors.forename: Christophe
authors.initials: C
authors.lastname: Simian
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Vidal-Petiot
authors.forename: Christelle
authors.initials: C
authors.lastname: Soukaseum
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.forename: Françoise
authors.initials: F
authors.lastname: Broux
authors.forename: Olivier
authors.initials: O
authors.lastname: Chabre
authors.forename: Michel
authors.initials: M
authors.lastname: Delahousse
authors.forename: Vincent
authors.initials: V
authors.lastname: Esnault
authors.forename: Béatrice
authors.initials: B
authors.lastname: Fiquet
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Corinne Isnard
authors.initials: CI
authors.lastname: Bagnis
authors.forename: Jens
authors.initials: J
authors.lastname: Koenig
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Paul
authors.initials: P
authors.lastname: Landais
authors.forename: Chebel
authors.initials: C
authors.lastname: Mourani
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Unwin
authors.forename: Steven D
authors.initials: SD
authors.lastname: Soroka
authors.forename: Georg
authors.initials: G
authors.lastname: Ehret
authors.forename: Stephan
authors.initials: S
authors.lastname: Ossowski
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D009399:Nephrons / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D049992:Sodium Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C489837:KLHL3 protein, human; D008840:Microfilament Proteins; D049992:Sodium Chloride Symporters