Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling
Copyright policy )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.
- University of California, San Diego United States
- DePaul University United States
- Harvard University United States
- Washington State University United States
- University Medical Center Freiburg Germany
570, DNA-Binding Proteins/metabolism*, Cystic/genetics*, 610, Genes, Recessive, DCN PAC - Perception action and control, NCMLS 6: Genetics and epigenetic pathways of disease, /dk/atira/pure/subjectarea/asjc/1300, Cystic, Mice, Cilia/metabolism, Zebrafish/metabolism, Recessive, Animals, Humans, Exome, Cilia, DNA Damage*, Zebrafish, MRE11 Homologue Protein, Biochemistry, Genetics and Molecular Biology(all), NCMLS 6: Genetics and epigenetic pathways of disease IGMD 9: Renal disorder, Proteins, Kidney Diseases, Cystic, DNA-Binding Proteins, Genes, Gene Knockdown Techniques, Microtubule Proteins, Zebrafish/embryology, Kidney Diseases, Microtubule Proteins/metabolism*, Exome*, DNA Damage, Signal Transduction
570, DNA-Binding Proteins/metabolism*, Cystic/genetics*, 610, Genes, Recessive, DCN PAC - Perception action and control, NCMLS 6: Genetics and epigenetic pathways of disease, /dk/atira/pure/subjectarea/asjc/1300, Cystic, Mice, Cilia/metabolism, Zebrafish/metabolism, Recessive, Animals, Humans, Exome, Cilia, DNA Damage*, Zebrafish, MRE11 Homologue Protein, Biochemistry, Genetics and Molecular Biology(all), NCMLS 6: Genetics and epigenetic pathways of disease IGMD 9: Renal disorder, Proteins, Kidney Diseases, Cystic, DNA-Binding Proteins, Genes, Gene Knockdown Techniques, Microtubule Proteins, Zebrafish/embryology, Kidney Diseases, Microtubule Proteins/metabolism*, Exome*, DNA Damage, Signal Transduction
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