DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN
DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN
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DOI：
10.1681/asn.2012090903
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发表时间：
2013-03-01
影响因子：
13.6
通讯作者：
Attanasio, Massimo
中科院分区：
文献类型：
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作者：
Ozaltin, Fatih;Li, Binghua;Attanasio, Massimo
肾微血管病变和膜增生性肾小球肾炎(MPGN)可以表现出相似的临床表现和组织学，提示在某些病例中可能存在共同的潜在机制。在这里，我们在一个土耳其血缘家庭中进行了纯合子作图和整个外显子组测序，并确定DGKE基因变异是膜增生性肾小球微血管病变的原因。此外，我们在142名被诊断为膜增生性肾小球肾炎的无关患者中发现了另外两个DGKE变异。该基因编码二酰基甘油激酶DGK epsilon，这是一种细胞内的脂酶，将二酰甘油磷酸化为磷脂酸。免疫荧光共聚焦显微镜显示，小鼠和大鼠DGK epsilon与足细胞标记WT1共存，但不与内皮标记CD31共存。人胚胎肾(HEK293)细胞膜片钳实验表明，DGK epsilon突变体影响细胞内二酰甘油的浓度。综上所述，这些结果不仅确定了肾小球微血管病变的遗传原因，还表明需要DGKE的磷脂酰肌醇循环对足细胞的正常功能至关重要。J Am Soc Nephrol 24：377-384,2013。DOI：10.1681/ASN.2012090903
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 DGK epsilon, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgk epsilon colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGK epsilon 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. J Am Soc Nephrol 24: 377-384, 2013. doi: 10.1681/ASN.2012090903