2012年8月13日 訊 /生物谷BIOON/ --在一項新研究中,，研究人員發(fā)現(xiàn)一個基因突變與慢性腎衰竭(chronic kidney failure)存在關(guān)聯(lián)。他們發(fā)現(xiàn)患有一種特定類型腎病---巨核間質(zhì)腎病(karyomegalic interstitial nephritis, KIN)的病人很可能在一種被稱作FAN1的特定基因上發(fā)生突變,。基因FAN1編碼一種有助修補DNA損傷的蛋白,。美國洛克菲勒大學(xué)助理教授Agata Smogorzewska和同事們提供證據(jù)證實基因FAN1突變和這種疾病之間存在因果關(guān)系,。
在這項新研究中，研究人員研究了基因FNA1突變是否腎病存在因果關(guān)系,。在一項測試中,，他們從病人體內(nèi)提取細胞，讓這些細胞接觸一種經(jīng)常被用于化療治療的藥物,，即絲裂霉素C(mitomycin C),。絲裂霉素C導(dǎo)致DNA發(fā)生交聯(lián)，即雙螺旋DNA雙鏈結(jié)合在一起以至于它們不能夠被分開,，從而使得它們不能夠復(fù)制和產(chǎn)生新的細胞,。已知FAN1修復(fù)這種DNA損傷。在實驗室中,，研究人員在這種藥物的存在下研究了病人的細胞,，他們觀察到大量的DNA損傷，這意味著在這些病人的細胞中,，F(xiàn)NA1不能正確地發(fā)揮作用,。當(dāng)把校正后的FAN1基因?qū)脒@些細胞時,，它們能夠恢復(fù)修復(fù)這種交聯(lián)損傷的能力。
盡管研究人員發(fā)現(xiàn)DNA損傷與腎衰竭存在關(guān)聯(lián),，但是人們?nèi)匀恍枰嗔私膺@種關(guān)聯(lián),。最初是什么導(dǎo)致這種DNA損傷，同時讓攜帶這種突變基因的病人不能修復(fù)它,？為什么這種損傷會影響腎臟但是不對其他器官產(chǎn)生影響,？Smogorzewska實驗室如今正在努力解答這些問題。(生物谷：Bioon.com)
本文編譯自Collaboration finds kidney disease tied to DNA damage
doi: 10.1038/ng.2347
PMC:
PMID:
FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair
Weibin Zhou, Edgar A Otto, Andrew Cluckey, Rannar Airik, Toby W Hurd, Moumita Chaki, Katrina Diaz, Francis P Lach, Geoffrey R Bennett, Heon Yung Gee, Amiya K Ghosh, Sivakumar Natarajan, Supawat Thongthip, Uma Veturi, Susan J Allen, Sabine Janssen, Gokul Ramaswami, Joanne Dixon, Felix Burkhalter, Martin Spoendlin, Holger Moch, Michael J Mihatsch, Jerome Verine, Richard Reade, Hany Soliman et al.
Chronic kidney disease (CKD) represents a major health burden1. 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 karyomegaly2. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway3, 4, 5, 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.
