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DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.

发布于：2013年5月6日    文字：【大】【中】【小】

J Am Soc Nephrol. 2013 Feb;24(3):377-84. doi: 10.1681/ASN.2012090903. Epub 2012 Dec 28.

DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.

Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N,Ashraf S, Du Y, Liang C, Chen P, Lu D, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M.

Source

Department of Pediatric Nephrology, HacettepeUniversityFaculty of Medicine,Ankara,Turkey.

Abstract

Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy.Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGKε, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgkεcolocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGKε variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

肾脏血栓性微血管病和膜增殖性生小球肾炎(TMA)在临床表现和病史方面有相似之处，这提示二者可能有相同的发病机制。本研究采用纯合子映射和外显子测序技术，在一个土耳其家族中发现了DGKE基因变异。这可能是肾小球膜增殖样血栓性微血管病的病因。接着我们在142例无血缘关系的MPGN患者中发现了另外两种DGKE基因变异。DGKE基因编码二酰基甘油激酶DGKε。DGKε为一种细胞内的脂质激酶，可以促使二酰基甘油磷酸化为磷脂酸。免疫荧光共聚焦显微镜证实了小鼠和大鼠的DGKε可以与足细胞的标志物WT1共定位，但是不能与内皮细胞标志物CD31共定位。在人胚肾细胞(HEK293)上行膜片钳技术显示，DGKε变异可以影响细胞内二酰基甘油的含量。以上研究表明，磷脂酰肌醇循环需要DGKE，DGKE是足细胞保持正常功能状态的重要调节分子。