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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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.

Author information

Author notes

    • Mathieu Lemaire
    •  & Véronique Frémeaux-Bacchi

    These authors contributed equally to this work.


  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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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.

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.

Corresponding authors

Correspondence to Véronique Frémeaux-Bacchi or Richard P Lifton.

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