• A Corrigendum to this article was published on 26 April 2012

This article has been updated

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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Change history

  • 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

    • Hélène Louis-Dit-Picard
    • , Julien Barc
    •  & Daniel Trujillano

    These authors contributed equally to this work.

    • Juliette Hadchouel
    • , Jean-Jacques Schott
    •  & Xavier Jeunemaitre

    These authors jointly directed this work.

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. Cardiology, Department of Specialties of Internal Medicine, 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

Consortia

  1. International Consortium for Blood Pressure (ICBP)

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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xavier Jeunemaitre.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1–3, 5 and 6 and Supplementary Note

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    Supplementary Table 4

    Association of common variants at the KLHL3 locus with blood pressure in healthy individuals

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DOI

https://doi.org/10.1038/ng.2218

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