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 Cervenka, Ranjani Sri Ganji, Vitezslav Bryja, Heleen H Arts, Jeroen van Reeuwijk, Machteld M Oud & 53 andre 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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftCell Stem Cell
Vol/bind150
Udgave nummer3
Sider (fra-til)533-48
Antal sider16
ISSN1934-5909
DOI
StatusUdgivet - 2012

Fingeraftryk

Exome
Kidney
Mutation
Kidney Diseases
Retina
Cilia
Zebrafish
DNA
Proteins

Citer dette

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 Stem Cell, 150(3), 533-48. 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 ; Cervenka, 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. I: Cell Stem Cell. 2012 ; Bind 150, Nr. 3. s. 533-48.
@article{762d49c615e442f1b5c9eee49ab8650d,
title = "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling",
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.",
keywords = "Animals, Cilia, DNA Damage, DNA-Binding Proteins, Exome, Gene Knockdown Techniques, Genes, Recessive, Humans, Kidney Diseases, Cystic, Mice, Microtubule Proteins, Signal Transduction, Zebrafish",
author = "Moumita Chaki and Rannar Airik and Ghosh, {Amiya K} and Giles, {Rachel H} and Rui Chen and Slaats, {Gisela G} and Hui Wang and Hurd, {Toby W} and Weibin Zhou and Andrew Cluckey and Gee, {Heon Yung} and Gokul Ramaswami and Chen-Jei Hong and Hamilton, {Bruce A} and Igor Cervenka and Ganji, {Ranjani Sri} and Vitezslav Bryja and Arts, {Heleen H} and {van Reeuwijk}, Jeroen and Oud, {Machteld M} and Letteboer, {Stef J F} and Ronald Roepman and Herv{\'e} Husson and Oxana Ibraghimov-Beskrovnaya and Takayuki Yasunaga and Gerd Walz and Lorraine Eley and Sayer, {John A} and Bernhard Schermer and Liebau, {Max C} and Thomas Benzing and {Le Corre}, Stephanie and Iain Drummond and Sabine Janssen and Allen, {Susan J} and Sivakumar Natarajan and O'Toole, {John F} and Massimo Attanasio and Sophie Saunier and Corinne Antignac and Koenekoop, {Robert K} and Huanan Ren and Irma Lopez and Ahmet Nayir and Corinne Stoetzel and Helene Dollfus and Rustin Massoudi and Gleeson, {Joseph G} and Andreoli, {Sharon P} and Doherty, {Dan G} and Anna Lindstrad and Christelle Golzio and Nicholas Katsanis and Lars Pape and Abboud, {Emad B} and Al-Rajhi, {Ali A} and Lewis, {Richard A} and Heymut Omran and Lee, {Eva Y-H P} and Shaohui Wang and Sekiguchi, {Joann M} and Rudel Saunders and Johnson, {Colin A} and Elizabeth Garner and Katja Vanselow and Andersen, {Jens S.} and Joseph Shlomai and Gudrun Nurnberg and Peter Nurnberg and Shawn Levy and Agata Smogorzewska and Otto, {Edgar A} and Friedhelm Hildebrandt",
note = "Copyright {\circledC} 2012 Elsevier Inc. All rights reserved.",
year = "2012",
doi = "10.1016/j.cell.2012.06.028",
language = "English",
volume = "150",
pages = "533--48",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",

}

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, C-J, Hamilton, BA, Cervenka, 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, EY-HP, 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 Stem Cell, bind 150, nr. 3, s. 533-48. 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; Cervenka, 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.

I: Cell Stem Cell, Bind 150, Nr. 3, 2012, s. 533-48.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - Cervenka, 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 P

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

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012

Y1 - 2012

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.

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.

KW - Animals

KW - Cilia

KW - DNA Damage

KW - DNA-Binding Proteins

KW - Exome

KW - Gene Knockdown Techniques

KW - Genes, Recessive

KW - Humans

KW - Kidney Diseases, Cystic

KW - Mice

KW - Microtubule Proteins

KW - Signal Transduction

KW - Zebrafish

U2 - 10.1016/j.cell.2012.06.028

DO - 10.1016/j.cell.2012.06.028

M3 - Journal article

VL - 150

SP - 533

EP - 548

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 3

ER -