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Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Nature Genetics volume 45, pages 531–536 (2013)Cite this article

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Abstract

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure1. Atypical HUS (aHUS) can result from genetic or autoimmune factors2 that lead to pathologic complement cascade activation3. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid–containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.

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Figure 1: Kidney biopsies of subjects with DGKE mutations show histological features of chronic thrombotic microangiopathy.
Figure 2: DGKE mutations in aHUS.
Figure 3: Clinical course of aHUS due to DGKE mutation.
Figure 4: DGKE protein is expressed in endothelium, platelets and podocytes.

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Acknowledgements

We thank the subjects with aHUS, their families and the health care professionals whose participation made this study possible; J. Zhang, C. Nelson-Williams, S. Mentone, D. Beury and other members of the complement laboratory at Hôpital Européen Georges-Pompidou for technical support; the staff of the Yale Center for Genome Analysis for exome sequencing; S. Ishibe, S. Shibata, U. Scholl, M.-A. Dragon-Durey, L. Roumenina, M. Malina, Q. Vincent and L. Abel for helpful discussions; and D. Damotte (Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Service d'Anatomie Pathologique) for the anti-CD34 staining. This work was supported by US National Institutes of Health (NIH) grants U54 HG006504 01 (Yale Center for Mendelian Genomics), P30 DK079310 05 (Yale O'Brien Center for Kidney Research) and UL1TR00142 07 (Yale Center for Translational Science Award), grants from the Délégation Régionale à la Recherche Clinique, Assistance Publique–Hôpitaux de Paris to V.F.-B., such as Programme Hospitalier de Recherche Clinique (AOM08198) and the Association pour l'Information et la Recherche dans les maladies Rénales génétiques (AIRG France), and a European Community FP7 Grant 2012-305608 (EURenOmics) to F.S. and V.F.-B. M.L. is the recipient of a Kidney Research Scientist Core Education and National Training (KRESCENT) Program Post-Doctoral Fellowship Award from the Kidney Foundation of Canada and is a member of the Investigative Medicine PhD program at Yale University School of Medicine.

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Author notes

  1. Mathieu Lemaire and Véronique Frémeaux-Bacchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Mathieu Lemaire, Murim Choi, Weizhen Ji, John D Overton, Shrikant M Mane & Richard P Lifton

  2. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Mathieu Lemaire, Murim Choi, Weizhen Ji & Richard P Lifton

  3. Department of Immunology, Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France

    Véronique Frémeaux-Bacchi

  4. Centre de Recherche des Cordeliers, Unité Mixte de Recherche en Santé (UMR-S) 872, Paris, France

    Véronique Frémeaux-Bacchi & Moglie Le Quintrec

  5. Division of Pediatric Nephrology, Heidelberg University Medical Center, Heidelberg, Germany

    Franz Schaefer

  6. Center for Pediatrics and Adolescent Medicine, Heidelberg University Medical Center, Heidelberg, Germany

    Franz Schaefer

  7. Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, USA

    Murim Choi, John D Overton, Shrikant M Mane & Richard P Lifton

  8. Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Wai Ho Tang & John Hwa

  9. Department of Nephrology, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France

    Fadi Fakhouri

  10. Department of Pediatrics, CHU Rennes, Rennes, France

    Sophie Taque

  11. Department of Pediatrics, CHU Besançon, Besançon, France

    François Nobili

  12. Department of Nephrology, Assistance Publique–Hôpitaux de Paris, Hôpital Necker–Enfants Malades, Paris, France

    Frank Martinez

  13. Cologne Center for Genomics, University of Cologne, Cologne, Germany

    Gudrun Nürnberg, Janine Altmüller, Holger Thiele & Peter Nürnberg

  14. Department of Pediatric Nephrology, CHU Montpellier, Montpellier, France

    Denis Morin

  15. Department of Pediatric Nephrology, Assistance Publique–Hôpitaux de Paris, Hôpital Universitaire Robert-Debré, Paris, France

    Georges Deschenes, Véronique Baudouin & Chantal Loirat

  16. Department of Pediatric Nephrology, CHU Bordeaux, Bordeaux, France

    Brigitte Llanas

  17. Department of Pediatrics, Centre Hospitalier Chrétien (CHC) Liège, Liège, Belgium

    Laure Collard

  18. Department of Pediatrics, Pediatric Nephrology Unit, Dubai Hospital, Dubai, United Arab Emirates

    Mohammed A Majid & Eva Simkova

  19. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Peter Nürnberg

  20. ATLAS Biolabs GmbH, Berlin, Germany

    Peter Nürnberg

  21. Department of Pathology, CHU Rennes, Rennes, France

    Nathalie Rioux-Leclerc

  22. Renal Pathology and Electron Microscopy Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA

    Gilbert W Moeckel

  23. Institut National de la Santé et de la Recherche Médicale (INSERM) U983, Hôpital Necker–Enfants Malades, Paris, France

    Marie Claire Gubler

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  1. Mathieu Lemaire
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Contributions

M.L., V.F.-B. and R.P.L. designed experiments and analyzed data. M.C. and R.P.L. developed the exome analysis protocol. S.M.M., J.D.O., J.A. and H.T. directed the exome capture, DNA sequencing infrastructure and information technology. M.C., M.L., R.P.L., G.N. and P.N. performed bioinformatic and statistical analyses. M.L., W.J. and R.P.L. analyzed the age of shared mutation. M.L., W.J. and V.F.-B. performed Sanger sequencing. W.H.T., J.H. and F.F. performed protein blotting experiments. M.L. performed the immunofluorescence studies. M.L.Q. and F.F. performed the immunohistochemistry studies on human kidneys. F.S., S.T., F.N., F.M., D.M., G.D., V.B., B.L., L.C., M.A.M., E.S. and C.L. ascertained and evaluated patients with aHUS. C.L., V.F.-B. and F.S. recruited patients with aHUS. N.R.-L., G.W.M. and M.C.G. provided renal pathology expertise. M.L., V.F.-B. and R.P.L. wrote the manuscript.

Corresponding authors

Correspondence to Véronique Frémeaux-Bacchi or Richard P Lifton.

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Competing interests

F.S., F.F., C.L. and V.F.-B. have received fees from Alexion Pharmaceuticals for invited lectures and are members of an expert board supported by Alexion Pharmaceuticals. C.L. is an unpaid coordinator for France for the clinical trial 'Eculizumab in atypical HUS'. P.N. is a founder, CEO and shareholder of ATLAS Biolabs GmbH, a service provider for genomic analyses.

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Lemaire, M., Frémeaux-Bacchi, V., Schaefer, F. et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45, 531–536 (2013). https://doi.org/10.1038/ng.2590

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