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FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.


ABSTRACT: 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.

SUBMITTER: Zhou W 

PROVIDER: S-EPMC3412140 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.

Zhou Weibin W   Otto Edgar A EA   Cluckey Andrew A   Airik Rannar R   Hurd Toby W TW   Chaki Moumita M   Diaz Katrina K   Lach Francis P FP   Bennett Geoffrey R GR   Gee Heon Yung HY   Ghosh Amiya K AK   Natarajan Sivakumar S   Thongthip Supawat S   Veturi Uma U   Allen Susan J SJ   Janssen Sabine S   Ramaswami Gokul G   Dixon Joanne J   Burkhalter Felix F   Spoendlin Martin M   Moch Holger H   Mihatsch Michael J MJ   Verine Jerome J   Reade Richard R   Soliman Hany H   Godin Michel M   Kiss Denes D   Monga Guido G   Mazzucco Gianna G   Amann Kerstin K   Artunc Ferruh F   Newland Ronald C RC   Wiech Thorsten T   Zschiedrich Stefan S   Huber Tobias B TB   Friedl Andreas A   Slaats Gisela G GG   Joles Jaap A JA   Goldschmeding Roel R   Washburn Joseph J   Giles Rachel H RH   Levy Shawn S   Smogorzewska Agata A   Hildebrandt Friedhelm F  

Nature genetics 20120708 8


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 withi  ...[more]

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