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

Hélène Louis-Dit-Picard, 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 BagnisJens 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, Patrick Bruneval, Xavier P. Estivill, Philippe Froguel, Juliette Hadchouel, Jean Jacques Schott, Xavier Jeunemaitre

Research output: Contribution to journalArticle

173 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)456-460
Number of pages5
JournalNature Genetics
Volume44
Issue number4
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

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Member 3 Solute Carrier Family 12
Nephrons
Ion Transport
Hypertension
Mutation
Blood Pressure
Exome
Microfilament Proteins
Missense Mutation
Ligases
Ubiquitin
Homeostasis
Down-Regulation
Ions
Phenotype
Genes
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Louis-Dit-Picard, H., Barc, J., Trujillano, D., Miserey-Lenkei, S., Bouatia-Naji, N., Pylypenko, O., ... Jeunemaitre, X. (2012). KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nature Genetics, 44(4), 456-460. https://doi.org/10.1038/ng.2218

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. / Louis-Dit-Picard, Hélène; Barc, Julien; Trujillano, Daniel; Miserey-Lenkei, Stéphanie; Bouatia-Naji, Nabila; Pylypenko, Olena; Beaurain, Geneviève; Bonnefond, Amélie; Sand, Olivier; Simian, Christophe; Vidal-Petiot, Emmanuelle; Soukaseum, Christelle; Mandet, Chantal; Broux, Françoise; Chabre, Olivier; Delahousse, Michel; Esnault, Vincent; Fiquet, Béatrice; Houillier, Pascal; Bagnis, Corinne Isnard; Koenig, Jens; Konrad, Martin; Landais, Paul; Mourani, Chebel; Niaudet, Patrick; Probst, Vincent; Thauvin, Christel; Unwin, Robert J.; Soroka, Steven D.; Ehret, Georg; Ossowski, Stephan; Caulfield, Mark; Bruneval, Patrick; Estivill, Xavier P.; Froguel, Philippe; Hadchouel, Juliette; Schott, Jean Jacques; Jeunemaitre, Xavier.

In: Nature Genetics, Vol. 44, No. 4, 04.2012, p. 456-460.

Research output: Contribution to journalArticle

Louis-Dit-Picard, H, Barc, J, Trujillano, D, Miserey-Lenkei, S, Bouatia-Naji, N, Pylypenko, O, Beaurain, G, Bonnefond, A, Sand, O, Simian, C, Vidal-Petiot, E, Soukaseum, C, Mandet, C, Broux, F, Chabre, O, Delahousse, M, Esnault, V, Fiquet, B, Houillier, P, Bagnis, CI, Koenig, J, Konrad, M, Landais, P, Mourani, C, Niaudet, P, Probst, V, Thauvin, C, Unwin, RJ, Soroka, SD, Ehret, G, Ossowski, S, Caulfield, M, Bruneval, P, Estivill, XP, Froguel, P, Hadchouel, J, Schott, JJ & Jeunemaitre, X 2012, 'KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron', Nature Genetics, vol. 44, no. 4, pp. 456-460. https://doi.org/10.1038/ng.2218
Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nature Genetics. 2012 Apr;44(4):456-460. https://doi.org/10.1038/ng.2218
Louis-Dit-Picard, Hélène ; Barc, Julien ; Trujillano, Daniel ; Miserey-Lenkei, Stéphanie ; Bouatia-Naji, Nabila ; Pylypenko, Olena ; Beaurain, Geneviève ; Bonnefond, Amélie ; Sand, Olivier ; Simian, Christophe ; Vidal-Petiot, Emmanuelle ; Soukaseum, Christelle ; Mandet, Chantal ; Broux, Françoise ; Chabre, Olivier ; Delahousse, Michel ; Esnault, Vincent ; Fiquet, Béatrice ; Houillier, Pascal ; Bagnis, Corinne Isnard ; Koenig, Jens ; Konrad, Martin ; Landais, Paul ; Mourani, Chebel ; Niaudet, Patrick ; Probst, Vincent ; Thauvin, Christel ; Unwin, Robert J. ; Soroka, Steven D. ; Ehret, Georg ; Ossowski, Stephan ; Caulfield, Mark ; Bruneval, Patrick ; Estivill, Xavier P. ; Froguel, Philippe ; Hadchouel, Juliette ; Schott, Jean Jacques ; Jeunemaitre, Xavier. / KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. In: Nature Genetics. 2012 ; Vol. 44, No. 4. pp. 456-460.
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AU - Louis-Dit-Picard, Hélène

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AU - Miserey-Lenkei, Stéphanie

AU - Bouatia-Naji, Nabila

AU - Pylypenko, Olena

AU - Beaurain, Geneviève

AU - Bonnefond, Amélie

AU - Sand, Olivier

AU - Simian, Christophe

AU - Vidal-Petiot, Emmanuelle

AU - Soukaseum, Christelle

AU - Mandet, Chantal

AU - Broux, Françoise

AU - Chabre, Olivier

AU - Delahousse, Michel

AU - Esnault, Vincent

AU - Fiquet, Béatrice

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AU - Bagnis, Corinne Isnard

AU - Koenig, Jens

AU - Konrad, Martin

AU - Landais, Paul

AU - Mourani, Chebel

AU - Niaudet, Patrick

AU - Probst, Vincent

AU - Thauvin, Christel

AU - Unwin, Robert J.

AU - Soroka, Steven D.

AU - Ehret, Georg

AU - Ossowski, Stephan

AU - Caulfield, Mark

AU - Bruneval, Patrick

AU - Estivill, Xavier P.

AU - Froguel, Philippe

AU - Hadchouel, Juliette

AU - Schott, Jean Jacques

AU - Jeunemaitre, Xavier

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