2. Academic Validation
  3. 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

  • Nat Genet. 2012 Jul 8;44(8):910-5. doi: 10.1038/ng.2347.
Weibin Zhou 1,  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,  Michel Godin,  Denes Kiss,  Guido Monga,  Gianna Mazzucco,  Kerstin Amann,  Ferruh Artunc,  Ronald C Newland,  Thorsten Wiech,  Stefan Zschiedrich,  Tobias B Huber,  Andreas Friedl,  Gisela G Slaats,  Jaap A Joles,  Roel Goldschmeding,  Joseph Washburn,  Rachel H Giles,  Shawn Levy,  Agata Smogorzewska,  Friedhelm Hildebrandt
Affiliations

Affiliation

  • 1 Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
PMID: 22772369 DOI: 10.1038/ng.2347
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.

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