Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling

被引：291

作者：

Chaki, Moumita ^{[1
]}

Airik, Rannar ^{[1
]}

Ghosh, Amiya K. ^{[1
]}

Giles, Rachel H. ^{[3
]}

Chen, Rui ^{[4
]}

Slaats, Gisela G. ^{[3
]}

Wang, Hui ^{[4
]}

Hurd, Toby W. ^{[1
]}

Zhou, Weibin ^{[1
]}

Cluckey, Andrew ^{[1
]}

Gee, Heon Yung ^{[1
]}

Ramaswami, Gokul ^{[1
]}

Hong, Chen-Jei ^{[6
,7
]}

Hamilton, Bruce A. ^{[6
,7
]}

Cervenka, Igor ^{[8
]}

Ganji, Ranjani Sri ^{[8
]}

Bryja, Vitezslav ^{[8
,9
]}

Arts, Heleen H. ^{[10
,11
]}

van Reeuwijk, Jeroen ^{[10
,11
]}

Oud, Machteld M. ^{[10
,11
]}

Letteboer, Stef J. F. ^{[10
,11
]}

Roepman, Ronald ^{[10
,11
]}

Husson, Herve ^{[12
]}

Ibraghimov-Beskrovnaya, Oxana ^{[12
]}

Yasunaga, Takayuki ^{[13
]}

Walz, Gerd ^{[13
]}

Eley, Lorraine ^{[14
]}

Sayer, John A. ^{[14
]}

Schermer, Bernhard ^{[15
,16
,17
,19
]}

Liebau, Max C. ^{[15
,16
,18
]}

Benzing, Thomas ^{[15
,16
,17
,19
]}

Le Corre, Stephanie ^{[22
,23
]}

Drummond, Iain ^{[22
,23
]}

Janssen, Sabine ^{[1
]}

Allen, Susan J. ^{[1
]}

Natarajan, Sivakumar ^{[1
]}

O'Toole, John F. ^{[24
,25
]}

Attanasio, Massimo ^{[26
,27
]}

Saunier, Sophie ^{[28
]}

Antignac, Corinne ^{[28
]}

Koenekoop, Robert K. ^{[29
]}

Ren, Huanan ^{[29
]}

Lopez, Irma ^{[29
]}

Nayir, Ahmet ^{[30
]}

Stoetzel, Corinne ^{[31
]}

Dollfus, Helene ^{[31
]}

Massoudi, Rustin ^{[32
]}

Gleeson, Joseph G. ^{[32
]}

Andreoli, Sharon P. ^{[33
]}

Doherty, Dan G. ^{[34
]}

机构：

[1] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[3] Univ Med Ctr, Dept Hypertens & Nephrol, Utrecht, Netherlands

[4] Baylor Coll Med, HGSC Dept Mol & Human Genet, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA

[6] Univ Calif San Diego, Sch Med, Dept Med, Div Med Genet,Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Sch Med, Inst Genom Med, George Palade Labs, La Jolla, CA 92093 USA

[8] Masaryk Univ, Fac Sci, Inst Expt Biol, CS-61137 Brno, Czech Republic

[9] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, CS-61265 Brno, Czech Republic

[10] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 GA Nijmegen, Netherlands

[12] Genzyme Corp, Cell Biol, Framingham, MA 01701 USA

[13] Univ Freiburg, Div Renal, Med Ctr, D-79001 Freiburg, Germany

[14] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[15] Univ Cologne, Dept Internal Med 2, D-50937 Cologne, Germany

[16] Univ Cologne, Ctr Mol Med, D-50937 Cologne, Germany

[17] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50937 Cologne, Germany

[18] Univ Cologne, Dept Pediat & Adolescent Med, D-50937 Cologne, Germany

[19] Univ Cologne, Syst Biol Aging, D-50937 Cologne, Germany

[20] Univ Cologne, Cologne Ctr Genom & Mol Med, D-50937 Cologne, Germany

[21] Hebrew Univ Hadassah Med Sch, Fac Med, Dept Microbiol & Mol Genet, IMRIC, IL-91120 Jerusalem, Israel

[22] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Nephrol Div, Charlestown, MA 02129 USA

[23] Harvard Univ, Sch Med, Dept Genet, Charlestown, MA 02129 USA

[24] Metrohlth Med Ctr, Dept Internal Med, Div Nephrol, Cleveland, OH 44109 USA

[25] Case Western Reserve Univ, Sch Med, Cleveland, OH 44109 USA

[26] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[27] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Growth & Dev, Dallas, TX 75390 USA

[28] Paris Descartes Univ, Hop Necker Enfants Malades, Inserm U983, AP HP, Paris, France

[29] McGill Univ, Montreal Childrens Hosp, McGill Ocular Genet Lab, Ctr Hlth, Montreal, PQ H3H 1P3, Canada

[30] Istanbul Univ, Fac Med, Dept Pediat Nephrol, Istanbul, Turkey

[31] Univ Strasbourg, Fac Med, Lab Genet Med EA3949, Equipe AVENIR Inserm, F-67000 Strasbourg, France

[32] Univ Calif San Diego, Howard Hughes Med Inst, Dept Pediat, La Jolla, CA 92093 USA

[33] Indiana Univ, James Whitcomb Riley Hosp Children, Dept Pediat, Med Ctr, Indianapolis, IN 46202 USA

[34] Univ Washington, Seattle Childrens Hosp, Dept Pediat, Div Genet Med,Ctr Integrat Brain Res, Seattle, WA 98101 USA

[35] Duke Univ, Ctr Human Dis Modeling, Med Ctr, Durham, NC 27710 USA

[36] Hannover Med Sch, Dept Pediat Nephrol, D-30625 Hannover, Germany

[37] King Khalid Eye Specialist Hosp, Riyadh 11462, Saudi Arabia

[38] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed Allgemeine Pad, D-48149 Munster, Germany

[39] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA

[40] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England

[41] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA

[42] Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark

[43] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[44] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2012年 / 150卷 / 03期

关键词：

MULTIPOINT LINKAGE ANALYSIS; POLYCYSTIC KIDNEY-DISEASE; ATAXIA-TELANGIECTASIA; SECKEL-SYNDROME; CENTROSOMAL PROTEIN; GENOMIC STABILITY; JOUBERT-SYNDROME; HUMAN-CELLS; GENE; MOUSE;

D O I：

10.1016/j.cell.2012.06.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：533 / 548

页数：16

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