Abstract
Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. PaperFlick:
| Original language | English |
|---|---|
| Pages (from-to) | 533-548 |
| Number of pages | 16 |
| Journal | Cell |
| Volume | 150 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 3 2012 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. / Chaki, Moumita; Airik, Rannar; Ghosh, Amiya K.; Giles, Rachel H.; Chen, Rui; Slaats, Gisela G.; Wang, Hui; Hurd, Toby W.; Zhou, Weibin; Cluckey, Andrew; Gee, Heon Yung; Ramaswami, Gokul; Hong, Chen Jei; Hamilton, Bruce A.; Červenka, Igor; Ganji, Ranjani Sri; Bryja, Vitezslav; Arts, Heleen H.; Van Reeuwijk, Jeroen; Oud, MacHteld M.; Letteboer, Stef J F; Roepman, Ronald; Husson, Hervé; Ibraghimov-Beskrovnaya, Oxana; Yasunaga, Takayuki; Walz, Gerd; Eley, Lorraine; Sayer, John A.; Schermer, Bernhard; Liebau, Max C.; Benzing, Thomas; Le Corre, Stephanie; Drummond, Iain; Janssen, Sabine; Allen, Susan J.; Natarajan, Sivakumar; O'Toole, John F.; Attanasio, Massimo; Saunier, Sophie; Antignac, Corinne; Koenekoop, Robert K.; Ren, Huanan; Lopez, Irma; Nayir, Ahmet; Stoetzel, Corinne; Dollfus, Helene; Massoudi, Rustin; Gleeson, Joseph G.; Andreoli, Sharon; Doherty, Dan G.; Lindstrad, Anna; Golzio, Christelle; Katsanis, Nicholas; Pape, Lars; Abboud, Emad B.; Al-Rajhi, Ali A.; Lewis, Richard A.; Omran, Heymut; Lee, Eva Y H P; Wang, Shaohui; Sekiguchi, Joann M.; Saunders, Rudel; Johnson, Colin A.; Garner, Elizabeth; Vanselow, Katja; Andersen, Jens S.; Shlomai, Joseph; Nurnberg, Gudrun; Nurnberg, Peter; Levy, Shawn; Smogorzewska, Agata; Otto, Edgar A.; Hildebrandt, Friedhelm.
In: Cell, Vol. 150, No. 3, 03.08.2012, p. 533-548.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling
AU - Chaki, Moumita
AU - Airik, Rannar
AU - Ghosh, Amiya K.
AU - Giles, Rachel H.
AU - Chen, Rui
AU - Slaats, Gisela G.
AU - Wang, Hui
AU - Hurd, Toby W.
AU - Zhou, Weibin
AU - Cluckey, Andrew
AU - Gee, Heon Yung
AU - Ramaswami, Gokul
AU - Hong, Chen Jei
AU - Hamilton, Bruce A.
AU - Červenka, Igor
AU - Ganji, Ranjani Sri
AU - Bryja, Vitezslav
AU - Arts, Heleen H.
AU - Van Reeuwijk, Jeroen
AU - Oud, MacHteld M.
AU - Letteboer, Stef J F
AU - Roepman, Ronald
AU - Husson, Hervé
AU - Ibraghimov-Beskrovnaya, Oxana
AU - Yasunaga, Takayuki
AU - Walz, Gerd
AU - Eley, Lorraine
AU - Sayer, John A.
AU - Schermer, Bernhard
AU - Liebau, Max C.
AU - Benzing, Thomas
AU - Le Corre, Stephanie
AU - Drummond, Iain
AU - Janssen, Sabine
AU - Allen, Susan J.
AU - Natarajan, Sivakumar
AU - O'Toole, John F.
AU - Attanasio, Massimo
AU - Saunier, Sophie
AU - Antignac, Corinne
AU - Koenekoop, Robert K.
AU - Ren, Huanan
AU - Lopez, Irma
AU - Nayir, Ahmet
AU - Stoetzel, Corinne
AU - Dollfus, Helene
AU - Massoudi, Rustin
AU - Gleeson, Joseph G.
AU - Andreoli, Sharon
AU - Doherty, Dan G.
AU - Lindstrad, Anna
AU - Golzio, Christelle
AU - Katsanis, Nicholas
AU - Pape, Lars
AU - Abboud, Emad B.
AU - Al-Rajhi, Ali A.
AU - Lewis, Richard A.
AU - Omran, Heymut
AU - Lee, Eva Y H P
AU - Wang, Shaohui
AU - Sekiguchi, Joann M.
AU - Saunders, Rudel
AU - Johnson, Colin A.
AU - Garner, Elizabeth
AU - Vanselow, Katja
AU - Andersen, Jens S.
AU - Shlomai, Joseph
AU - Nurnberg, Gudrun
AU - Nurnberg, Peter
AU - Levy, Shawn
AU - Smogorzewska, Agata
AU - Otto, Edgar A.
AU - Hildebrandt, Friedhelm
PY - 2012/8/3
Y1 - 2012/8/3
N2 - Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. PaperFlick:
AB - Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. PaperFlick:
UR - http://www.scopus.com/inward/record.url?scp=84864584531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864584531&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.06.028
DO - 10.1016/j.cell.2012.06.028
M3 - Article
C2 - 22863007
AN - SCOPUS:84864584531
VL - 150
SP - 533
EP - 548
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -