Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
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DOI：
10.1038/ng.2590
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发表时间：
2013-05
期刊：
影响因子：
30.8
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Lemaire, Mathieu;Fremeaux-Bacchi, Veronique;Schaefer, Franz;Choi, Murim;Tang, Wai Ho;Le Quintrec, Moglie;Fakhouri, Fadi;Taque, Sophie;Nobili, Franois;Martinez, Frank;Ji, Weizhen;Overton, John D.;Mane, Shrikant M.;Nuernberg, Gudrun;Altmueller, Janine;Thiele, Holger;Morin, Denis;Deschenes, Georges;Baudouin, Veronique;Llanas, Brigitte;Collard, Laure;Majid, Mohammed A.;Simkova, Eva;Nuernberg, Peter;Rioux-Leclercq, Nathalie;Moeckel, Gilbert W.;Gubler, Marie Claire;Hwa, John;Loirat, Chantal;Lifton, Richard P.
病理性血栓形成是死亡的主要原因。溶血性尿毒症综合征（HUS）的特征是小血管血栓形成，导致微血管病性溶血性贫血、血小板减少和肾衰竭。非典型HUS（阿胡斯）可由导致病理性补体级联激活的遗传或自身免疫因素引起。通过外显子组测序，我们确定了DGKE（二酰甘油激酶）的隐性突变，与9个无关的激酶中的阿胡斯共分离，定义了一个独特的孟德尔疾病。受影响的患者在1岁前出现阿胡斯，具有持续性高血压、血尿和蛋白尿（有时为肾病范围），并随着年龄的增长发展为慢性肾病。DGKE存在于内皮、血小板和足细胞中。含花生四烯酸的二酰基甘油（DAG）激活蛋白激酶C，促进血栓形成。DGKE通常停用DAG信令。我们推断DGKE功能的丧失导致血栓前状态。这些发现确定了病理性血栓形成和肾衰竭的新机制，并对阿胡斯患者的治疗具有直接意义。
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. By exome sequencing we identify recessive mutations in DGKE (diacylglycerol kinase epsilon) that co-segregate with aHUS in 9 unrelated kindreds, defining a distinctive Mendelian disease. Affected patients present with aHUS before age 1, have persistent hypertension, hematuria and proteinuria (sometimes 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, which promotes thrombosis. DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a pro-thrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treatment of aHUS patients.
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影响因子：
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