FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair
FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair
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DOI：
10.1038/ng.2347
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发表时间：
2012-08-01
期刊：
影响因子：
30.8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Zhou, Weibin;Otto, Edgar A.;Hildebrandt, Friedhelm
慢性肾脏疾病（CKD）是一个主要的健康负担(1)。其主要特征肾纤维化尚不清楚。通过外显子组测序，我们发现FAN1突变是导致核肥大性间质性肾炎（KIN）的原因之一，这种疾病是肾纤维化的一种模型。除了存在核肿大外，KIN的肾脏组织学与肾性肾病难以区分(2)。FAN1蛋白具有核酸酶活性，在Fanconi贫血DNA损伤反应（DDR）途径中参与DNA链间交联（ICL）修复（3-6）。我们发现，来自Fanconi贫血个体的细胞与来自Fanconi贫血个体的细胞不同，来自FAN1突变个体的细胞对icl诱导剂丝裂霉素C具有敏感性，但在二氧丁烷处理后不会出现染色体断裂或细胞周期停滞。我们用野生型FAN1补充ICL敏感性，但不使用在KIN个体中发现突变的cDNA。在斑马鱼中，fan1的缺失导致DDR增加、细胞凋亡和肾囊肿。我们的研究结果表明，对环境基因毒素的易感性和DNA修复不足是导致肾纤维化和慢性肾病的新机制。
Chronic kidney disease (CKD) represents a major health burden(1). Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly(2). The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway(3-6). We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.