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Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling.
Airik, Rannar; Slaats, Gisela G; Guo, Zhi; Weiss, Anna-Carina; Khan, Naheed; Ghosh, Amiya; Hurd, Toby W; Bekker-Jensen, Simon; Schrøder, Jacob M; Elledge, Steve J; Andersen, Jens S; Kispert, Andreas; Castelli, Maddalena; Boletta, Alessandra; Giles, Rachel H; Hildebrandt, Friedhelm.
Afiliación
  • Airik R; Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts;
  • Slaats GG; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands;
  • Guo Z; Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts;
  • Weiss AC; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany;
  • Khan N; Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan;
  • Ghosh A; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
  • Hurd TW; Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom;
  • Bekker-Jensen S; Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
  • Schrøder JM; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;
  • Elledge SJ; Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts;
  • Andersen JS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;
  • Kispert A; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany;
  • Castelli M; Division of Genetics and Cell Biology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy; and.
  • Boletta A; Division of Genetics and Cell Biology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy; and.
  • Giles RH; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands;
  • Hildebrandt F; Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland Friedhelm.Hildebrandt@childrens.harvard.edu.
J Am Soc Nephrol ; 25(11): 2573-83, 2014 Nov.
Article en En | MEDLINE | ID: mdl-24722439
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autoantígenos / Daño del ADN / Transducción de Señal / Enfermedades Renales Quísticas / Proteínas de Neoplasias Límite: Animals Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2014 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autoantígenos / Daño del ADN / Transducción de Señal / Enfermedades Renales Quísticas / Proteínas de Neoplasias Límite: Animals Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2014 Tipo del documento: Article