Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

Moumita Chaki, Rannar Airik, Amiya K. Ghosh, Rachel H. Giles, Rui Chen, Gisela G. Slaats, Hui Wang, Toby W. Hurd, Weibin Zhou, Andrew Cluckey, Heon Yung Gee, Gokul Ramaswami, Chen Jei Hong, Bruce A. Hamilton, Igor Červenka, Ranjani Sri Ganji, Vitezslav Bryja, Heleen H. Arts, Jeroen Van Reeuwijk, MacHteld M. Oud & 53 others Stef J F Letteboer, Ronald Roepman, Hervé Husson, Oxana Ibraghimov-Beskrovnaya, Takayuki Yasunaga, Gerd Walz, Lorraine Eley, John A. Sayer, Bernhard Schermer, Max C. Liebau, Thomas Benzing, Stephanie Le Corre, Iain Drummond, Sabine Janssen, Susan J. Allen, Sivakumar Natarajan, John F. O'Toole, Massimo Attanasio, Sophie Saunier, Corinne Antignac, Robert K. Koenekoop, Huanan Ren, Irma Lopez, Ahmet Nayir, Corinne Stoetzel, Helene Dollfus, Rustin Massoudi, Joseph G. Gleeson, Sharon P. Andreoli, Dan G. Doherty, Anna Lindstrad, Christelle Golzio, Nicholas Katsanis, Lars Pape, Emad B. Abboud, Ali A. Al-Rajhi, Richard A. Lewis, Heymut Omran, Eva Y H P Lee, Shaohui Wang, Joann M. Sekiguchi, Rudel Saunders, Colin A. Johnson, Elizabeth Garner, Katja Vanselow, Jens S. Andersen, Joseph Shlomai, Gudrun Nurnberg, Peter Nurnberg, Shawn Levy, Agata Smogorzewska, Edgar A. Otto, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

189 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)533-548
Number of pages16
JournalCell
Volume150
Issue number3
DOIs
StatePublished - Aug 3 2012

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Exome
DNA Damage
Kidney
Mutation
DNA
Kidney Diseases
Retina
Genes
Centrosome
Cilia
Zebrafish
Automatic teller machines
Ciliopathies
Brain
Phenotype
Defects
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chaki, M., Airik, R., Ghosh, A. K., Giles, R. H., Chen, R., Slaats, G. G., ... Hildebrandt, F. (2012). Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell, 150(3), 533-548. https://doi.org/10.1016/j.cell.2012.06.028

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 P.; 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 journalArticle

Chaki, M, Airik, R, Ghosh, AK, Giles, RH, Chen, R, Slaats, GG, Wang, H, Hurd, TW, Zhou, W, Cluckey, A, Gee, HY, Ramaswami, G, Hong, CJ, Hamilton, BA, Červenka, I, Ganji, RS, Bryja, V, Arts, HH, Van Reeuwijk, J, Oud, MM, Letteboer, SJF, Roepman, R, Husson, H, Ibraghimov-Beskrovnaya, O, Yasunaga, T, Walz, G, Eley, L, Sayer, JA, Schermer, B, Liebau, MC, Benzing, T, Le Corre, S, Drummond, I, Janssen, S, Allen, SJ, Natarajan, S, O'Toole, JF, Attanasio, M, Saunier, S, Antignac, C, Koenekoop, RK, Ren, H, Lopez, I, Nayir, A, Stoetzel, C, Dollfus, H, Massoudi, R, Gleeson, JG, Andreoli, SP, Doherty, DG, Lindstrad, A, Golzio, C, Katsanis, N, Pape, L, Abboud, EB, Al-Rajhi, AA, Lewis, RA, Omran, H, Lee, EYHP, Wang, S, Sekiguchi, JM, Saunders, R, Johnson, CA, Garner, E, Vanselow, K, Andersen, JS, Shlomai, J, Nurnberg, G, Nurnberg, P, Levy, S, Smogorzewska, A, Otto, EA & Hildebrandt, F 2012, 'Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling', Cell, vol. 150, no. 3, pp. 533-548. https://doi.org/10.1016/j.cell.2012.06.028
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 P. ; 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. / Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. In: Cell. 2012 ; Vol. 150, No. 3. pp. 533-548.
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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:",
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AU - Chaki, Moumita

AU - Airik, Rannar

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AU - Giles, Rachel H.

AU - Chen, Rui

AU - Slaats, Gisela G.

AU - Wang, Hui

AU - Hurd, Toby W.

AU - Zhou, Weibin

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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

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AU - Gleeson, Joseph G.

AU - Andreoli, Sharon P.

AU - Doherty, Dan G.

AU - Lindstrad, Anna

AU - Golzio, Christelle

AU - Katsanis, Nicholas

AU - Pape, Lars

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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.

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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

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