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

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.

Pubmed ID: 22863007

Authors

  • 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
  • Cervenka I
  • Ganji RS
  • Bryja V
  • Arts HH
  • van Reeuwijk J
  • Oud MM
  • Letteboer SJ
  • 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
  • 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

Journal

Cell

Publication Data

August 3, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK068306
  • Agency: NIDDK NIH HHS, Id: DK072301
  • Agency: NIDDK NIH HHS, Id: DK075972
  • Agency: NIDDK NIH HHS, Id: DK090917
  • Agency: NIDDK NIH HHS, Id: DK091405
  • Agency: NEI NIH HHS, Id: F32EY19430
  • Agency: Medical Research Council, Id: G0700073
  • Agency: NICHD NIH HHS, Id: HD042601
  • Agency: NIDDK NIH HHS, Id: K99 DK091405
  • Agency: NINDS NIH HHS, Id: NS054871
  • Agency: NINDS NIH HHS, Id: NS060109
  • Agency: NIDDK NIH HHS, Id: R01 DK068306
  • Agency: NIDDK NIH HHS, Id: R01 DK072301
  • Agency: NIDDK NIH HHS, Id: R01 DK075972
  • Agency: NIDDK NIH HHS, Id: R01 DK076683
  • Agency: NIDDK NIH HHS, Id: R01 DK088767
  • Agency: NEI NIH HHS, Id: R01 EY018571
  • Agency: NICHD NIH HHS, Id: R01 HD042601
  • Agency: NEI NIH HHS, Id: R01EY018571
  • Agency: NCRR NIH HHS, Id: S10 RR026550
  • Agency: NHGRI NIH HHS, Id: U54 HG003273
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cilia
  • DNA Damage
  • DNA-Binding Proteins
  • Exome
  • Gene Knockdown Techniques
  • Genes, Recessive
  • Humans
  • Kidney Diseases, Cystic
  • Mice
  • Microtubule Proteins
  • Signal Transduction
  • Zebrafish