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

Nature Genetics volume 44, pages 456–460 (2012)Cite this article

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A Corrigendum to this article was published on 26 April 2012

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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.

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Figure 1: Combined linkage analysis and whole-exome sequencing in two FHHt pedigrees identified mutations in KLHL3.
Figure 2: Localization of altered residues in KLHL3.
Figure 3: KLHL3 is expressed in the distal nephron.
Figure 4: KLHL3 is associated with the actin cytoskeleton and interacts with and regulates NCC plasma membrane expression.

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  • 22 March 2012

    In the version of this article initially published, two references were omitted, resulting in several statements being incorrectly attributed in the Online Methods. In the 'Ped01' subsection of the 'Whole-exome sequencing' section, two statements were attributed to ref. 21. The correct reference for these statements has been added as ref. 27. In the 'Ped02' subsection of the 'Whole-exome sequencing' section, Annovar was incorrectly attributed to ref. 22. The correct reference has been added as ref. 28. As a result of the addition of these two references, former refs. 27-36 have been renumbered as refs. 29-38, respectively, in the text and reference list. In addition, author affiliation 7 was incorrectly given as Genes and Disease Program, Center for Genomic Regulation (CGR), Pompeu Fabra University, Barcelona, Spain. The correct affiliation is Genes and Disease Program, Center for Genomic Regulation (CGR) and Pompeu Fabra University, Barcelona, Spain. Similarly, affiliation 32 was incorrectly given as Genomic and Epigenetic Variation in Disease Group, Center for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain. The correct affiliation is Genomic and Epigenetic Variation in Disease Group, CGR and Pompeu Fabra University, Barcelona, Spain. These corrections have been made in the HTML and PDF versions of the article.

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Acknowledgements

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).

Author information

Author notes

  1. Hélène Louis-Dit-Picard, Julien Barc, Daniel Trujillano and Philippe Froguel: These authors contributed equally to this work.

  2. Juliette Hadchouel, Jean-Jacques Schott and Xavier Jeunemaitre: These authors jointly directed this work.

Authors and Affiliations

  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

    Hélène Louis-Dit-Picard, Nabila Bouatia-Naji, Geneviève Beaurain, Emmanuelle Vidal-Petiot, Christelle Soukaseum, Chantal Mandet, Patrick Bruneval, Juliette Hadchouel & Xavier Jeunemaitre

  2. Faculty of Medicine, Université Paris Descartes, Pôle de Recherche et d'Enseignement Supérieur (PRES) Sorbonne Paris Cité, Paris, France

    Hélène Louis-Dit-Picard, Nabila Bouatia-Naji, Geneviève Beaurain, Emmanuelle Vidal-Petiot, Christelle Soukaseum, Chantal Mandet, Pascal Houillier, Paul Landais, Patrick Niaudet, Patrick Bruneval, Juliette Hadchouel & Xavier Jeunemaitre

  3. Département de Génétique, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou (HEGP), Paris, France

    Hélène Louis-Dit-Picard, Geneviève Beaurain, Christophe Simian & Xavier Jeunemaitre

  4. INSERM, Unité Mixte de Recherche (UMR) 1087, Institut du Thorax, Université de Nantes, Nantes, France

    Julien Barc, Vincent Probst & Jean-Jacques Schott

  5. Faculty of Medicine, Université de Nantes, Nantes, France

    Julien Barc, Vincent Probst & Jean-Jacques Schott

  6. Centre National de la Recherche Scientifique (CNRS), Équipe de Recherche Labellisée (ERL) 3147, Nantes, France

    Julien Barc, Vincent Probst & Jean-Jacques Schott

  7. Genes and Disease Program, Center for Genomic Regulation (CGR) and Pompeu Fabra University, Barcelona, Spain

    Daniel Trujillano, Xavier Estivill & Jean-Jacques Schott

  8. Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Spain

    Daniel Trujillano & Xavier Estivill

  9. CNRS, UMR 144, Institut Curie, Paris, France

    Stéphanie Miserey-Lenkei & Olena Pylypenko

  10. CNRS, UMR 8199, Lille Pasteur Institute, Lille, France

    Amélie Bonnefond, Olivier Sand & Philippe Froguel

  11. Faculty of Medicine, Lille Nord de France University, Lille, France

    Amélie Bonnefond, Olivier Sand & Philippe Froguel

  12. Département de Pédiatrie Médicale, Centre Hospitalier Universitaire (CHU) Charles Nicolle, Université de Rouen, Rouen, France

    Françoise Broux

  13. CHU de Grenoble, Université Joseph Fourier, Grenoble, France

    Olivier Chabre

  14. Département de Nephrologie, Hopital Foch, Suresnes, France

    Michel Delahousse

  15. Service de Néphrologie, CHU de Nice, Hôpital Pasteur, Nice, France

    Vincent Esnault

  16. Faculty of Medicine, Université de Nice Sophia Antipolis, Nice, France

    Vincent Esnault

  17. Service d'Hypertension et Médecine Vasculaire, AP-HP, HEGP, Paris, France

    Béatrice Fiquet

  18. Service d'Explorations Fonctionnelles Rénales, AP-HP, HEGP, Paris, France

    Pascal Houillier

  19. INSERM, UMR S872–Institut des Cordeliers, Paris, France

    Pascal Houillier

  20. Nephrology Department, AP-HP, Hôpital Pitié-Salpétrière, Paris, France

    Corinne Isnard Bagnis

  21. Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany

    Jens Koenig & Martin Konrad

  22. Services de Néphrologie et Néphrologie Pédiatrique, AP-HP, Hôpital Necker, Paris, France

    Paul Landais & Patrick Niaudet

  23. INSERM, U507, Hôpital Necker, Paris, France

    Paul Landais

  24. Departement de Pediatrie, Hotel Dieu de France, Beirut, Lebanon

    Chebel Mourani

  25. Service de Cardiologie Nantes, CHU de Nantes, Institut du Thorax, Nantes, France

    Vincent Probst & Jean-Jacques Schott

  26. CHU de Dijon, Centre de Génétique, Dijon, France

    Christel Thauvin

  27. Faculté de Médecine, Université de Bourgogne, Dijon, France

    Christel Thauvin

  28. Centre for Nephrology, University College London Medical School, Royal Free Campus and Hospital, London, UK

    Robert J Unwin

  29. Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

    Steven D Soroka

  30. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Georg Ehret

  31. Department of Specialties of Internal Medicine, Cardiology, Geneva University, Geneva, Switzerland

    Georg Ehret

  32. Genomic and Epigenomic Variation in Disease Group, CGR and Pompeu Fabra University, Barcelona, Spain

    Stephan Ossowski

  33. Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Mark Caulfield

  34. Service d'Anatomo Pathologie, AP-HP, HEGP, Paris, France

    Patrick Bruneval

  35. Department of Health and Life Sciences, Pompeu Fabra University, Barcelona, Spain

    Xavier Estivill

  36. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK

    Philippe Froguel

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  1. Hélène Louis-Dit-Picard
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Consortia

International Consortium for Blood Pressure (ICBP)

Contributions

H.L.-D.-P. designed, performed and analyzed the data of the genetic analyses and immunoblotting experiments, and wrote the corresponding parts of the manuscript. J.B. designed, performed and analyzed the data of the genetic analyses (Ped02). D.T. together with S.O. and X.E. designed, performed and analyzed the WES of the Ped02 kindred. S.M.-L. designed and performed the in vitro and immunofluorescence experiments, and wrote the corresponding parts of the manuscript. N.B.-N. designed the WES for the Ped01 kindred and participated in the interpretation of the genetic analyses (exome sequencing of Ped01 and association studies) and in the writing of the manuscript. O.P. designed, performed and analyzed KLHL3 modeling and the prediction of the consequences of KLHL3 mutations. G.B. participated in the collection of the families with FHHt and to the analysis of previous candidate genes. V.E. collected and characterized the first members of the Nantes FHHt family. A.B. contributed to the WES of Ped01. O.S. performed the bioinformatics analyses of WES in Ped01. C. Simian performed the sequencing of hypertensive and normotensive individuals. E.V.-P. designed, performed and analyzed the qRT-PCR experiments. C. Soukaseum provided technical help to H.L.-D.-P. C. Mandet performed the immunohistochemistry. F.B., O.C., M.D., B.F., P.H., J.K., M.K., P.L., C. Mourani, P.N., V.P., C.T., R.J.U., S.D.S. and C.I.B. recruited families with FHHt. G.E. and M.C. designed, performed and analyzed the association study of KLHL3 and blood pressure within the ICBP. P.B. designed and analyzed the immunohistochemistry experiments. P.F. designed and analyzed WES. J.-J.S. designed and analyzed the genetic study and wrote the corresponding parts of the manuscript. X.J. and J.H. designed the study, analyzed data and co-wrote the manuscript. X.J. organized the entire study.

Corresponding author

Correspondence to Xavier Jeunemaitre.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–3, 5 and 6 and Supplementary Note (PDF 21357 kb)

Supplementary Table 4

Association of common variants at the KLHL3 locus with blood pressure in healthy individuals (XLS 255 kb)

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Louis-Dit-Picard, H., Barc, J., Trujillano, D. et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 44, 456–460 (2012). https://doi.org/10.1038/ng.2218

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