Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
Nat Genet. 2012 Jul 8;44(8):910-5. doi: 10.1038/ng.2347.
Chronic kidney disease (CKD) represents a major health burden. 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. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. 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.
慢性肾脏病（CKD）是一个主要的健康负担。其肾纤维化的核心特征尚未被很好地理解。通过外显子组测序，我们发现 FAN1 中的突变是巨细胞间质性肾炎（KIN）的一个原因，KIN 是一种作为肾纤维化模型的疾病。KIN 的肾脏组织学与肾性骨营养不良症无法区分，除了存在巨细胞。FAN1 蛋白具有核酸酶活性，并在范可尼贫血 DNA 损伤反应（DDR）途径中的 DNA 链间交联（ICL）修复中起作用。我们表明，具有 FAN1 突变的个体的细胞对 ICL 诱导剂丝裂霉素 C 敏感，但在用二环氧丁烷处理后不像具有范可尼贫血的个体的细胞那样表现出染色体断裂或细胞周期停滞。我们用野生型 FAN1 而非具有 KIN 个体中发现的突变的 cDNA 来补充 ICL 敏感性。在斑马鱼中耗尽 fan1 会导致 DDR、细胞凋亡和肾脏囊肿增加。我们的研究结果表明，对环境遗传毒物的敏感性和不充分的 DNA 修复是导致肾纤维化和 CKD 的新机制。
