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; 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

doi:10.1016/j.cell.2012.06.028

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. OudStef 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

Department of Pharmacology

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

268 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 language	English
Pages (from-to)	533-548
Number of pages	16
Journal	Cell
Volume	150
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2012.06.028
Publication status	Published - 2012 Aug 3

Bibliographical note

Funding Information:
We are grateful to the study individuals for their contributions. This research was supported by grants from the NIH to F.H. (DK068306, DK090917), B.A.H (NS054871, NS060109), N.K. (HD042601, DK075972, DK072301), and W.Z. (DK091405); the March of Dimes Foundation and the Center for Organogenesis of the University of Michigan to F.H.; the Netherlands Organization for Scientific Research to R.R. (NWO Vidi-91786396) and R.H.G. (NWO Vidi-917.66.354), the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et Déficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007, and the Association Bardet-Biedl, France to H.D. and C.S.; the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA (to R.H.G., G.G.S., N.K., R.R., H.O., C.A.J. and G.W.); the Dutch Kidney Foundation (KJPB09.009 and IP11.58 to H.H.A); the Retina Research Foundation and the National Eye Institute (R01EY018571) to R.C.; the NIH to H.W. (F32EY19430); and the DFG (SCHE1562 and SFB832 to B.S.; SFB829 to T.B.; SFB592 to H.O.). R.K.K. is supported by FFB-Canada, CIHR, FRSQ, and Reseau Vision. J.S.A. is supported by the Lundbeck Foundation. V.B. is supported by MSM0021622430 (Ministry of Education, Youth and Sports of the Czech Republic), 204/09/H058, and 204/09/0498 (Czech Science Foundation) and EMBO Installation Grant; I.C. is supported by the programme, Brno PhD Talent of South Moravian Center for International Mobility. S.S. is a laureate of the “Equipe FRM” (DEQ20071210558) and the Agence National de la Recherche (R09087KS, R11012KK). W.Z. is a Carl. W. Gottschalk research scholar of the American Society of Nephrology. J.A.S. is a GlaxoSmithKline clinician scientist. A.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Doris Duke Charitable Foundation Clinical Scientist Development Awards and is a Rita Allen Foundation and an Irma T. Hirschl scholar. F.H. is an Investigator of the Howard Hughes Medical Institute, a Frederick G. L. Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2012.06.028

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Chaki, M., Airik, R., Ghosh, A. K., Giles, R. H., Chen, R., Slaats, G. G., Wang, H., Hurd, T. W., Zhou, W., Cluckey, A., Gee, H. Y., Ramaswami, G., Hong, C. J., Hamilton, B. A., Červenka, I., Ganji, R. S., Bryja, V., Arts, H. H., Van Reeuwijk, J., ... 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

@article{f5dc28a2d5e047feacbee3c2de2df506,

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. PaperFlick:",

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 Hong, {Chen Jei} and Hamilton, {Bruce A.} and Igor {\v C}ervenka 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 = "Funding Information: We are grateful to the study individuals for their contributions. This research was supported by grants from the NIH to F.H. (DK068306, DK090917), B.A.H (NS054871, NS060109), N.K. (HD042601, DK075972, DK072301), and W.Z. (DK091405); the March of Dimes Foundation and the Center for Organogenesis of the University of Michigan to F.H.; the Netherlands Organization for Scientific Research to R.R. (NWO Vidi-91786396) and R.H.G. (NWO Vidi-917.66.354), the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et D{\'e}ficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007, and the Association Bardet-Biedl, France to H.D. and C.S.; the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA (to R.H.G., G.G.S., N.K., R.R., H.O., C.A.J. and G.W.); the Dutch Kidney Foundation (KJPB09.009 and IP11.58 to H.H.A); the Retina Research Foundation and the National Eye Institute (R01EY018571) to R.C.; the NIH to H.W. (F32EY19430); and the DFG (SCHE1562 and SFB832 to B.S.; SFB829 to T.B.; SFB592 to H.O.). R.K.K. is supported by FFB-Canada, CIHR, FRSQ, and Reseau Vision. J.S.A. is supported by the Lundbeck Foundation. V.B. is supported by MSM0021622430 (Ministry of Education, Youth and Sports of the Czech Republic), 204/09/H058, and 204/09/0498 (Czech Science Foundation) and EMBO Installation Grant; I.C. is supported by the programme, Brno PhD Talent of South Moravian Center for International Mobility. S.S. is a laureate of the “Equipe FRM” (DEQ20071210558) and the Agence National de la Recherche (R09087KS, R11012KK). W.Z. is a Carl. W. Gottschalk research scholar of the American Society of Nephrology. J.A.S. is a GlaxoSmithKline clinician scientist. A.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Doris Duke Charitable Foundation Clinical Scientist Development Awards and is a Rita Allen Foundation and an Irma T. Hirschl scholar. F.H. is an Investigator of the Howard Hughes Medical Institute, a Frederick G. L. Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist. ",

year = "2012",

month = aug,

day = "3",

doi = "10.1016/j.cell.2012.06.028",

language = "English",

volume = "150",

pages = "533--548",

journal = "Cell",

issn = "0092-8674",

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, 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

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 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 - Funding Information: We are grateful to the study individuals for their contributions. This research was supported by grants from the NIH to F.H. (DK068306, DK090917), B.A.H (NS054871, NS060109), N.K. (HD042601, DK075972, DK072301), and W.Z. (DK091405); the March of Dimes Foundation and the Center for Organogenesis of the University of Michigan to F.H.; the Netherlands Organization for Scientific Research to R.R. (NWO Vidi-91786396) and R.H.G. (NWO Vidi-917.66.354), the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et Déficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007, and the Association Bardet-Biedl, France to H.D. and C.S.; the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA (to R.H.G., G.G.S., N.K., R.R., H.O., C.A.J. and G.W.); the Dutch Kidney Foundation (KJPB09.009 and IP11.58 to H.H.A); the Retina Research Foundation and the National Eye Institute (R01EY018571) to R.C.; the NIH to H.W. (F32EY19430); and the DFG (SCHE1562 and SFB832 to B.S.; SFB829 to T.B.; SFB592 to H.O.). R.K.K. is supported by FFB-Canada, CIHR, FRSQ, and Reseau Vision. J.S.A. is supported by the Lundbeck Foundation. V.B. is supported by MSM0021622430 (Ministry of Education, Youth and Sports of the Czech Republic), 204/09/H058, and 204/09/0498 (Czech Science Foundation) and EMBO Installation Grant; I.C. is supported by the programme, Brno PhD Talent of South Moravian Center for International Mobility. S.S. is a laureate of the “Equipe FRM” (DEQ20071210558) and the Agence National de la Recherche (R09087KS, R11012KK). W.Z. is a Carl. W. Gottschalk research scholar of the American Society of Nephrology. J.A.S. is a GlaxoSmithKline clinician scientist. A.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Doris Duke Charitable Foundation Clinical Scientist Development Awards and is a Rita Allen Foundation and an Irma T. Hirschl scholar. F.H. is an Investigator of the Howard Hughes Medical Institute, a Frederick G. L. Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist.

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:

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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

SN - 0092-8674

VL - 150

SP - 533

EP - 548

JO - Cell

JF - Cell

IS - 3

ER -

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

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