2. Academic Validation
  3. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

  • Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218.
Hélène Louis-Dit-Picard 1,  Julien Barc,  Daniel Trujillano,  Stéphanie Miserey-Lenkei,  Nabila Bouatia-Naji,  Olena Pylypenko,  Geneviève Beaurain,  Amélie Bonnefond,  Olivier Sand,  Christophe Simian,  Emmanuelle Vidal-Petiot,  Christelle Soukaseum,  Chantal Mandet,  Françoise Broux,  Olivier Chabre,  Michel Delahousse,  Vincent Esnault,  Béatrice Fiquet,  Pascal Houillier,  Corinne Isnard Bagnis,  Jens Koenig,  Martin Konrad,  Paul Landais,  Chebel Mourani,  Patrick Niaudet,  Vincent Probst,  Christel Thauvin,  Robert J Unwin,  Steven D Soroka,  Georg Ehret,  Stephan Ossowski,  Mark Caulfield,  International Consortium for Blood Pressure (ICBP),  Patrick Bruneval,  Xavier Estivill,  Philippe Froguel,  Juliette Hadchouel,  Jean-Jacques Schott,  Xavier Jeunemaitre
Affiliations

Affiliation

  • 1 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.
PMID: 22406640 DOI: 10.1038/ng.2218
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.

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