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 & 24 others 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

Research output: Contribution to journalArticle

115 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)910-915
Number of pages6
JournalNature Genetics
Volume44
Issue number8
DOIs
Publication statusPublished - 2012 Aug 1

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Interstitial Nephritis
DNA Repair
DNA Damage
Chronic Kidney Failure
Kidney
Mutation
Fanconi Anemia
Fibrosis
Chronic Renal Insufficiency
Exome
Chromosome Breakage
Mutagens
Mitomycin
Zebrafish
Cell Cycle Checkpoints
Cysts
Histology
Complementary DNA
Apoptosis
DNA

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., ... Hildebrandt, F. (2012). FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nature Genetics, 44(8), 910-915. https://doi.org/10.1038/ng.2347
Zhou, Weibin ; Otto, Edgar A. ; Cluckey, Andrew ; Airik, Rannar ; Hurd, Toby W. ; Chaki, Moumita ; Diaz, Katrina ; Lach, Francis P. ; Bennett, Geoffrey R. ; Gee, Heon Yung ; Ghosh, Amiya K. ; Natarajan, Sivakumar ; Thongthip, Supawat ; Veturi, Uma ; Allen, Susan J. ; Janssen, Sabine ; Ramaswami, Gokul ; Dixon, Joanne ; Burkhalter, Felix ; Spoendlin, Martin ; Moch, Holger ; Mihatsch, Michael J. ; Verine, Jerome ; Reade, Richard ; Soliman, Hany ; Godin, Michel ; Kiss, Denes ; Monga, Guido ; Mazzucco, Gianna ; Amann, Kerstin ; Artunc, Ferruh ; Newland, Ronald C. ; Wiech, Thorsten ; Zschiedrich, Stefan ; Huber, Tobias B. ; Friedl, Andreas ; Slaats, Gisela G. ; Joles, Jaap A. ; Goldschmeding, Roel ; Washburn, Joseph ; Giles, Rachel H. ; Levy, Shawn ; Smogorzewska, Agata ; Hildebrandt, Friedhelm. / FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. In: Nature Genetics. 2012 ; Vol. 44, No. 8. pp. 910-915.
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Zhou, W, Otto, EA, Cluckey, A, Airik, R, Hurd, TW, Chaki, M, Diaz, K, Lach, FP, Bennett, GR, Gee, HY, Ghosh, AK, Natarajan, S, Thongthip, S, Veturi, U, Allen, SJ, Janssen, S, Ramaswami, G, Dixon, J, Burkhalter, F, Spoendlin, M, Moch, H, Mihatsch, MJ, Verine, J, Reade, R, Soliman, H, Godin, M, Kiss, D, Monga, G, Mazzucco, G, Amann, K, Artunc, F, Newland, RC, Wiech, T, Zschiedrich, S, Huber, TB, Friedl, A, Slaats, GG, Joles, JA, Goldschmeding, R, Washburn, J, Giles, RH, Levy, S, Smogorzewska, A & Hildebrandt, F 2012, 'FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair', Nature Genetics, vol. 44, no. 8, pp. 910-915. https://doi.org/10.1038/ng.2347

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. / Zhou, Weibin; Otto, Edgar A.; Cluckey, Andrew; Airik, Rannar; Hurd, Toby W.; Chaki, Moumita; Diaz, Katrina; Lach, Francis P.; Bennett, Geoffrey R.; Gee, Heon Yung; Ghosh, Amiya K.; Natarajan, Sivakumar; Thongthip, Supawat; Veturi, Uma; Allen, Susan J.; Janssen, Sabine; Ramaswami, Gokul; Dixon, Joanne; Burkhalter, Felix; Spoendlin, Martin; Moch, Holger; Mihatsch, Michael J.; Verine, Jerome; Reade, Richard; Soliman, Hany; Godin, Michel; Kiss, Denes; Monga, Guido; Mazzucco, Gianna; Amann, Kerstin; Artunc, Ferruh; Newland, Ronald C.; Wiech, Thorsten; Zschiedrich, Stefan; Huber, Tobias B.; Friedl, Andreas; Slaats, Gisela G.; Joles, Jaap A.; Goldschmeding, Roel; Washburn, Joseph; Giles, Rachel H.; Levy, Shawn; Smogorzewska, Agata; Hildebrandt, Friedhelm.

In: Nature Genetics, Vol. 44, No. 8, 01.08.2012, p. 910-915.

Research output: Contribution to journalArticle

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AU - Janssen, Sabine

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AU - Dixon, Joanne

AU - Burkhalter, Felix

AU - Spoendlin, Martin

AU - Moch, Holger

AU - Mihatsch, Michael J.

AU - Verine, Jerome

AU - Reade, Richard

AU - Soliman, Hany

AU - Godin, Michel

AU - Kiss, Denes

AU - Monga, Guido

AU - Mazzucco, Gianna

AU - Amann, Kerstin

AU - Artunc, Ferruh

AU - Newland, Ronald C.

AU - Wiech, Thorsten

AU - Zschiedrich, Stefan

AU - Huber, Tobias B.

AU - Friedl, Andreas

AU - Slaats, Gisela G.

AU - Joles, Jaap A.

AU - Goldschmeding, Roel

AU - Washburn, Joseph

AU - Giles, Rachel H.

AU - Levy, Shawn

AU - Smogorzewska, Agata

AU - Hildebrandt, Friedhelm

PY - 2012/8/1

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N2 - 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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