FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.
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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: NAT GENET, Vol. 44, No. 8, 8, 2012, p. 910-915.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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
PY - 2012
Y1 - 2012
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.
KW - Animals
KW - Humans
KW - Genes, Recessive
KW - Gene Knockdown Techniques
KW - Cell Line
KW - Mutation
KW - DNA Damage
KW - Genetic Complementation Test
KW - DNA Repair/genetics
KW - Exodeoxyribonucleases/genetics
KW - Fanconi Anemia Complementation Group D2 Protein/genetics
KW - Nephritis, Interstitial/complications/genetics/metabolism/pathology
KW - Renal Insufficiency, Chronic/etiology/genetics/metabolism
KW - Zebrafish/abnormalities/genetics
KW - Animals
KW - Humans
KW - Genes, Recessive
KW - Gene Knockdown Techniques
KW - Cell Line
KW - Mutation
KW - DNA Damage
KW - Genetic Complementation Test
KW - DNA Repair/genetics
KW - Exodeoxyribonucleases/genetics
KW - Fanconi Anemia Complementation Group D2 Protein/genetics
KW - Nephritis, Interstitial/complications/genetics/metabolism/pathology
KW - Renal Insufficiency, Chronic/etiology/genetics/metabolism
KW - Zebrafish/abnormalities/genetics
M3 - SCORING: Journal article
VL - 44
SP - 910
EP - 915
JO - NAT GENET
JF - NAT GENET
SN - 1061-4036
IS - 8
M1 - 8
ER -
