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Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.

发布于：2013年5月6日    文字：【大】【中】【小】

Nat Genet. 2013 Apr 26;45(5):531-6. doi: 10.1038/ng.2590. Epub 2013 Mar 31.

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.

Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC,Hwa J, Loirat C, Lifton RP.

Source

1] Department of Genetics, YaleUniversitySchoolof Medicine,New Haven,Connecticut,USA. [2] Howard Hughes Medical Institute,YaleUniversitySchoolof Medicine,New Haven,Connecticut,USA. [3].

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 fators that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ?) 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.

病理血栓形成是临床主要死因。溶血尿毒综合征(HUS)的特点为发作性的小血管血栓形成，可以导致微血管溶血性贫血、血小板降低和肾衰竭。不典型HUS(aHUS)的病因可能为基因或者免疫性因素，这些因素可能通过激活补体系统而起致病作用。通过应用外显子测序技术，我们在9个不同源的家族中发现了多种DGKE基因突变，定义了一种新的孟德尔遗传病。受累患者在1岁钱就表现为aHUS，随着年龄的增长，高血压、贫血和蛋白尿(可为肾病范围)可以发展为慢性肾脏病。DGKE存在于内皮细胞、血小板和足细胞中。含花生四烯酸的二酰基甘油(DAG)可以激活蛋白激酶C(PKC)，继而引发血栓。DGKE可以抑制DAG信号转导。我们推测DGKE功能失调可能引发前血栓状态。这些发现提示一种新的病理血栓形成和肾衰的机制，为aHUS的治疗提供了新的启示。