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

John A. Sayer, Edgar A. Otto, John F. O'Toole, Gudrun Nurnberg, Michael A. Kennedy, Christian Becker, Hans Christian Hennies, Juliana Helou, Massimo Attanasio, Blake V. Fausett, Boris Utsch, Hemant Khanna, Yan Liu, Iain Drummond, Isao Kawakami, Takehiro Kusakabe, Motoyuki Tsuda, Li Ma, Hwankyu Lee, Ronald G. LarsonSusan J. Allen, Christopher J. Wilkinson, Erich A. Nigg, Chengchao Shou, Concepcion Lillo, David S. Williams, Bernd Hoppe, Markus J. Kemper, Thomas Neuhaus, Melissa A. Parisi, Ian A. Glass, Marianne Petry, Andreas Kispert, Joachim Gloy, Athina Ganner, Gerd Walz, Xueliang Zhu, Daniel Goldman, Peter Nurnberg, Anand Swaroop, Michel R. Leroux, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

472 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)674-681
Number of pages8
JournalNature Genetics
Issue number6
Publication statusPublished - 1 Jun 2006
Externally publishedYes


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