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 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; Patrick Bruneval; Xavier Estivill; Philippe Froguel; Juliette Hadchouel; Jean Jacques Schott; Xavier Jeunemaitre

doi:10.1038/ng.2218

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 Estivill, Philippe Froguel, Juliette Hadchouel, Jean Jacques Schott, Xavier Jeunemaitre

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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 language	English (US)
Pages (from-to)	456-460
Number of pages	5
Journal	Nature genetics
Volume	44
Issue number	4
DOIs	https://doi.org/10.1038/ng.2218
State	Published - Apr 2012
Externally published	Yes

ASJC Scopus subject areas

Genetics

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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., ... 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

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, X, 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

@article{a498c221bc094fd4996faddbc6b25181,

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.",

author = "H{\'e}l{\`e}ne Louis-Dit-Picard and Julien Barc and Daniel Trujillano and St{\'e}phanie Miserey-Lenkei and Nabila Bouatia-Naji and Olena Pylypenko and Genevi{\`e}ve Beaurain and Am{\'e}lie Bonnefond and Olivier Sand and Christophe Simian and Emmanuelle Vidal-Petiot and Christelle Soukaseum and Chantal Mandet and Fran{\c c}oise Broux and Olivier Chabre and Michel Delahousse and Vincent Esnault and B{\'e}atrice Fiquet and Pascal Houillier and Bagnis, {Corinne Isnard} and Jens Koenig and Martin Konrad and Paul Landais and Chebel Mourani and Patrick Niaudet and Vincent Probst and Christel Thauvin and Unwin, {Robert J.} and Soroka, {Steven D.} and Georg Ehret and Stephan Ossowski and Mark Caulfield and Patrick Bruneval and Xavier Estivill and Philippe Froguel and Juliette Hadchouel and Schott, {Jean Jacques} and Xavier Jeunemaitre",

note = "Funding Information: We thank C. B{\"u}sst for her critical reading of the manuscript, E. Clauser, F. Aurad{\'e} and C. Auzan for helpful discussions, E. Durand, S. Lecointe and F. De Graeve for their contribution to whole-exome sequencing and M. Long{\'e}p{\'e}e-Dupas for assistance in family screening. This work was supported by INSERM, the Agence Nationale pour la Recherche (ANR; 05-MRAR-010-01), the European Union Framework Programme 7 through the HYPERGENE project (HEALTH-F4-2007-201550) and through the GEUVADIS project (HEALTH-261123), the Leducq Foundation (Transatlantic Network on Hypertension; 07 CVD 01), the Fondation Leducq Trans-Atlantic Network of Excellence (05 CVD 01; Preventing Sudden Death), the Groupe de R{\'e}flexion sur la Recherche Cardiovasculaire and Biotronik and the Ministry of Science and Innovation (MICINN; SAF2008-00357).",

year = "2012",

month = apr,

doi = "10.1038/ng.2218",

language = "English (US)",

volume = "44",

pages = "456--460",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

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TY - JOUR

T1 - KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

AU - Louis-Dit-Picard, Hélène

AU - Barc, Julien

AU - Trujillano, Daniel

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

AU - Houillier, Pascal

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

AU - Froguel, Philippe

AU - Hadchouel, Juliette

AU - Schott, Jean Jacques

AU - Jeunemaitre, Xavier

N1 - Funding Information: We thank C. Büsst for her critical reading of the manuscript, E. Clauser, F. Auradé and C. Auzan for helpful discussions, E. Durand, S. Lecointe and F. De Graeve for their contribution to whole-exome sequencing and M. Longépée-Dupas for assistance in family screening. This work was supported by INSERM, the Agence Nationale pour la Recherche (ANR; 05-MRAR-010-01), the European Union Framework Programme 7 through the HYPERGENE project (HEALTH-F4-2007-201550) and through the GEUVADIS project (HEALTH-261123), the Leducq Foundation (Transatlantic Network on Hypertension; 07 CVD 01), the Fondation Leducq Trans-Atlantic Network of Excellence (05 CVD 01; Preventing Sudden Death), the Groupe de Réflexion sur la Recherche Cardiovasculaire and Biotronik and the Ministry of Science and Innovation (MICINN; SAF2008-00357).

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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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U2 - 10.1038/ng.2218

DO - 10.1038/ng.2218

M3 - Article

C2 - 22406640

AN - SCOPUS:84859425383

SN - 1061-4036

VL - 44

SP - 456

EP - 460

JO - Nature genetics

JF - Nature genetics

IS - 4

ER -

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

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