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 SpoendlinHolger 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

Research output: Contribution to journalArticlepeer-review

169 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)910-915
Number of pages6
JournalNature Genetics
Issue number8
Publication statusPublished - 2012 Aug

Bibliographical note

Funding Information:
We are grateful to the families and study individuals for their contribution. We thank A. Francois (Rouen) for contribution of pathology data and J. Amatruda (UT Southwestern) for antibodies. This research was supported by grants from the US National Institutes of Health to F.H. (DK068306), E.A.O. (DK090917) and W.Z. (DK091405), by the Burroughs Wellcome Fund Career Award for Medical Scientists and by Doris Duke Charitable Foundation Clinical Scientist Development Awards to A.S. W.Z. is a Carl W. Gottschalk Scholar of the American Society of Nephrology (ASN). A.S. is a Rita Allen Foundation Scholar and an Irma T. Hirschl Scholar. F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G.L. Huetwell Professor. This research was supported by grants from the European Union Seventh Framework Programme FP7/2009 under grant agreement 241955, SYSCILIA and the Netherlands Organization for Scientific Research to R.H.G. (NWO Vidi-917.66.354). This work used two Core facilities at the Michigan Diabetes Research and Training Center funded by DK020572 from the US National Institute of Diabetes and Digestive and Kidney Diseases.

All Science Journal Classification (ASJC) codes

  • Genetics


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