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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NCBI Reference Sequence
NCBI Reference Sequence
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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.
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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