Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling.
Nephronophthisis-related ciliopathies (NPHP-RCs) are developmental and degenerative kidney diseases that are frequently associated with extrarenal pathologies such as retinal degeneration, obesity, and intellectual disability. We recently identified mutations in a gene encoding the centrosomal protein SDCCAG8 as causing NPHP type 10 in humans. To study the role of Sdccag8 in disease pathogenesis, we generated a Sdccag8 gene-trap mouse line. Homozygous Sdccag8(gt/gt) mice lacked the wild-type Sdccag8 transcript and protein, and recapitulated the human phenotypes of NPHP and retinal degeneration. These mice exhibited early onset retinal degeneration that was associated with rhodopsin mislocalization in the photoreceptors and reduced cone cell numbers, and led to progressive loss of vision. By contrast, renal histologic changes occurred later, and no global ciliary defects were observed in the kidneys. Instead, renal pathology was associated with elevated levels of DNA damage response signaling activity. Cell culture studies confirmed the aberrant activation of DNA damage response in Sdccag8(gt/gt)-derived cells, characterized by elevated levels of γH2AX and phosphorylated ATM and cell cycle profile abnormalities. Our analysis of Sdccag8(gt/gt) mice indicates that the pleiotropic phenotypes in these mice may arise through multiple tissue-specific disease mechanisms.
Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts;
Rannar
R
Airik
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands;
Gisela G
GG
Slaats
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts;
Zhi
Z
Guo
Institute of Molecular Biology, Hannover Medical School, Hannover, Germany;
Anna-Carina
AC
Weiss
Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan;
Naheed
N
Khan
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
Amiya
A
Ghosh
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom;
Toby W
TW
Hurd
Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
Simon
S
Bekker-Jensen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;
Jacob M
JM
Schrøder
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts;
Steve J
SJ
Elledge
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;
Jens S
JS
Andersen
Institute of Molecular Biology, Hannover Medical School, Hannover, Germany;
Andreas
A
Kispert
Division of Genetics and Cell Biology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy; and.
Maddalena
M
Castelli
Division of Genetics and Cell Biology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy; and.
Alessandra
A
Boletta
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands;
Rachel H
RH
Giles
Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland Friedhelm.Hildebrandt@childrens.harvard.edu.
Friedhelm
F
Hildebrandt
D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D002460:Cell Line; D002461:Cell Line, Transformed; D002923:Cilia / Q000473:pathology; D004249:DNA Damage / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007668:Kidney / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
D001324:Autoantigens; D009363:Neoplasm Proteins; C472381:Sdccag8 protein, mouse; D049452:Green Fluorescent Proteins