6533b82bfe1ef96bd128e0bf
RESEARCH PRODUCT
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron
Daniel TrujillanoPatrick NiaudetPatrick NiaudetAmélie BonnefondAmélie BonnefondXavier JeunemaitreXavier JeunemaitrePascal HouillierPascal HouillierOlivier SandOlivier SandMark J. CaulfieldGeneviève BeaurainGeneviève BeaurainStéphanie Miserey-lenkeiPaul LandaisPaul LandaisRobert J. UnwinGeorg EhretGeorg EhretChebel MouraniOlivier ChabreVincent L.m. EsnaultCorinne Isnard BagnisChristophe SimianJuliette HadchouelJuliette HadchouelPatrick BrunevalPatrick BrunevalStephan OssowskiBéatrice FiquetChristelle SoukaseumChristelle SoukaseumHélène Louis-dit-picardHélène Louis-dit-picardChristel ThauvinEmmanuelle Vidal-petiotEmmanuelle Vidal-petiotJulien BarcJulien BarcOlena PylypenkoSteven D. SorokaNabila Bouatia-najiNabila Bouatia-najiMichel DelahoussePhilippe FroguelPhilippe FroguelPhilippe FroguelJean-jacques SchottXavier EstivillJens KoenigChantal MandetChantal MandetVincent ProbstMartin KonradFrançoise Brouxsubject
MaleCarrier Proteins/geneticsPseudohypoaldosteronism/genetics/metabolism/physiopathologyPseudohypoaldosteronism[SDV]Life Sciences [q-bio]Blood Pressure030204 cardiovascular system & hematologyNephrons/metabolismKidney0302 clinical medicineMissense mutationChildComputingMilieux_MISCELLANEOUSGeneticsddc:616Aged 80 and over0303 health sciencesbiologyMicrofilament ProteinsMiddle AgedWNK1PhenotypeSodium Chloride SymportersWNK4Ubiquitin ligaseFemaleSignal TransductionAdultmedicine.medical_specialtyAdolescentBlood Pressure/geneticsIon Transport/geneticsMolecular Sequence DataPolymorphism Single Nucleotide03 medical and health sciencesYoung AdultInternal medicineGeneticsmedicineHumansAmino Acid SequenceSodium Chloride Symporters/genetics/metabolism030304 developmental biologyAdaptor Proteins Signal TransducingAgedIon TransportBase Sequenceurogenital systemPseudohypoaldosteronismKidney metabolismNephronsSequence Analysis DNAmedicine.diseaseKidney/metabolismEndocrinologyIon homeostasisbiology.proteinCarrier Proteinsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-04-01 |