期刊
NATURE GENETICS
卷 45, 期 5, 页码 531-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2590
关键词
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资金
- US National Institutes of Health (NIH) [U54 HG006504 01, P30 DK079310 05, UL1TR00142 07]
- Delegation Regionale a la Recherche Clinique
- Assistance Publique-Hopitaux de Paris
- Programme Hospitalier de Recherche Clinique [AOM08198]
- Association pour l'Information et la Recherche dans les maladies Renales genetiques (AIRG France)
- European Community [2012-305608]
- Kidney Foundation of Canada
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(1). Atypical HUS (aHUS) can result from genetic or autoimmune factors(2) that lead to pathologic complement cascade activation(3). Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase epsilon) 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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