title: 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.
authors: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Weibin
authors: W
authors: Zhou
authors: Edgar A
authors: EA
authors: Otto
authors: Andrew
authors: A
authors: Cluckey
authors: Rannar
authors: R
authors: Airik
authors: Toby W
authors: TW
authors: Hurd
authors: Moumita
authors: M
authors: Chaki
authors: Katrina
authors: K
authors: Diaz
authors: Francis P
authors: FP
authors: Lach
authors: Geoffrey R
authors: GR
authors: Bennett
authors: Heon Yung
authors: HY
authors: Gee
authors: Amiya K
authors: AK
authors: Ghosh
authors: Sivakumar
authors: S
authors: Natarajan
authors: Supawat
authors: S
authors: Thongthip
authors: Uma
authors: U
authors: Veturi
authors: Susan J
authors: SJ
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authors: Sabine
authors: S
authors: Janssen
authors: Gokul
authors: G
authors: Ramaswami
authors: Joanne
authors: J
authors: Dixon
authors: Felix
authors: F
authors: Burkhalter
authors: Martin
authors: M
authors: Spoendlin
authors: Holger
authors: H
authors: Moch
authors: Michael J
authors: MJ
authors: Mihatsch
authors: Jerome
authors: J
authors: Verine
authors: Richard
authors: R
authors: Reade
authors: Hany
authors: H
authors: Soliman
authors: Michel
authors: M
authors: Godin
authors: Denes
authors: D
authors: Kiss
authors: Guido
authors: G
authors: Monga
authors: Gianna
authors: G
authors: Mazzucco
authors: Kerstin
authors: K
authors: Amann
authors: Ferruh
authors: F
authors: Artunc
authors: Ronald C
authors: RC
authors: Newland
authors: Thorsten
authors: T
authors: Wiech
authors: Stefan
authors: S
authors: Zschiedrich
authors: Tobias B
authors: TB
authors: Huber
authors: Andreas
authors: A
authors: Friedl
authors: Gisela G
authors: GG
authors: Slaats
authors: Jaap A
authors: JA
authors: Joles
authors: Roel
authors: R
authors: Goldschmeding
authors: Joseph
authors: J
authors: Washburn
authors: Rachel H
authors: RH
authors: Giles
authors: Shawn
authors: S
authors: Levy
authors: Agata
authors: A
authors: Smogorzewska
authors: Friedhelm
authors: F
authors: Hildebrandt
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D055785:Gene Knockdown Techniques; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D006801:Humans; D064251:Multifunctional Enzymes; D009154:Mutation; D009395:Nephritis, Interstitial / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000002:abnormalities / Q000235:genetics
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human