Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

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Item Type:	Article
Title:	Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome
Creators Name:	Lemaire, M., Frémeaux-Bacchi, V., Schaefer, F., Choi, M., Tang, W.H., Le Quintrec, M., Fakhouri, F., Taque, S., Nobili, F., Martinez, F., Ji, W., Overton, J.D., Mane, S.M., Nürnberg, G., Altmüller, J., Thiele, H., Morin, D., Deschenes, G., Baudouin, V., Llanas, B., Collard, L., Majid, M.A., Simkova, E., Nürnberg, P., Rioux-Leclerc, N., Moeckel, G.W., Gubler, M.C., Hwa, J., Loirat, C. and Lifton, R.P.
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 failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. 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.
Keywords:	Acute Kidney Injury, Atypical Hemolytic Uremic Syndrome, Preschool Child, Diacylglycerol Kinase, Exome, Recessive Genes, Hemolytic-Uremic Syndrome, Immunoenzyme Techniques, Molecular Sequence Data, Mutation, Chronic Renal Insufficiency, Thrombocytopenia, Thrombotic Microangiopathies
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	45
Number:	5
Page Range:	531-536
Date:	May 2013
Official Publication:	https://doi.org/10.1038/ng.2590
PubMed:	View item in PubMed

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