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; 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

doi:10.1038/ng.2347

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

189 Scopus citations

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 language	English (US)
Pages (from-to)	910-915
Number of pages	6
Journal	Nature genetics
Volume	44
Issue number	8
DOIs	https://doi.org/10.1038/ng.2347
State	Published - Aug 2012

ASJC Scopus subject areas

Genetics

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Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., Thongthip, S., Veturi, U., Allen, S. J., Janssen, S., Ramaswami, G., Dixon, J., Burkhalter, F., ... 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, 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

@article{3d3ff8815ba341caa264b508fbefc8e0,

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.",

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

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.",

year = "2012",

month = aug,

doi = "10.1038/ng.2347",

language = "English (US)",

volume = "44",

pages = "910--915",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

AU - Zhou, Weibin

AU - Otto, Edgar A.

AU - Cluckey, Andrew

AU - Airik, Rannar

AU - Hurd, Toby W.

AU - Chaki, Moumita

AU - Diaz, Katrina

AU - Lach, Francis P.

AU - Bennett, Geoffrey R.

AU - Gee, Heon Yung

AU - Ghosh, Amiya K.

AU - Natarajan, Sivakumar

AU - Thongthip, Supawat

AU - Veturi, Uma

AU - Allen, Susan J.

AU - Janssen, Sabine

AU - Ramaswami, Gokul

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

N1 - 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.

PY - 2012/8

Y1 - 2012/8

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.

AB - 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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JO - Nature genetics

JF - Nature genetics

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

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