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The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

Item Type:Article
Title:The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4
Creators Name:Sayer, J.A. and Otto, E.A. and O'toole, J.F. and Nuernberg, G. and Kennedy, M.A. and Becker, C. and Hennies, H.C. and Helou, J. and Attanasio, M. and Fausett, B.V. and Utsch, B. and Khanna, H. and Liu, Y. and Drummond, I. and Kawakami, I. and Kusakabe, T. and Tsuda, M. and Ma, L. and Lee, H. and Larson, R.G. and Allen, S.J. and Wilkinson, C.J. and Nigg, E.A. and Shou, C. and Lillo, C. and Williams, D.S. and Hoppe, B. and Kemper, M.J. and Neuhaus, T. and Parisi, M.A. and Glass, I.A. and Petry, M. and Kispert, A. and Gloy, J. and Ganner, A. and Walz, G. and Zhu, X. and Goldman, D. and Nuernberg, P. and Swaroop, A. and Leroux, M.R. and Hildebrandt, F.
Abstract:The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
Keywords:Activating Transcription Factor 4, Genetic Linkage, In Situ Hybridization, Mutation, Neoplasm Antigens, Neoplasm Proteins, Pedigree, Syndrome, Animals, Zebrafish
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:674-681
Date:June 2006
Official Publication:https://doi.org/10.1038/ng1786
PubMed:View item in PubMed

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