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

被引:428
作者
Sayer, John A.
Otto, Edgar A.
O'Toole, John F.
Nurnberg, Gudrun
Kennedy, Michael A.
Becker, Christian
Hennies, Hans Christian
Helou, Juliana
Attanasio, Massimo
Fausett, Blake V.
Utsch, Boris
Khanna, Hemant
Liu, Yan
Drummond, Iain
Kawakami, Isao
Kusakabe, Takehiro
Tsuda, Motoyuki
Ma, Li
Lee, Hwankyu
Larson, Ronald G.
Allen, Susan J.
Wilkinson, Christopher J.
Nigg, Erich A.
Shou, Chengchao
Lillo, Concepcion
Williams, David S.
Hoppe, Bernd
Kemper, Markus J.
Neuhaus, Thomas
Parisi, Melissa A.
Glass, Ian A.
Petry, Marianne
Kispert, Andreas
Gloy, Joachim
Ganner, Athina
Walz, Gerd
Zhu, Xueliang
Goldman, Daniel
Nurnberg, Peter
Swaroop, Anand
Leroux, Michel R.
Hildebrandt, Friedhelm [1 ]
机构
[1] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA
[2] Newcastle Univ, Sch Clin Med Sci, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
[3] Univ Cologne, Cologne Ctr Genom, D-5000 Cologne 41, Germany
[4] RZPD Deutsch Ressourcectr Genomforsch, Berlin, Germany
[5] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada
[6] Univ Michigan, Inst Biol Chem, Ann Arbor, MI 48109 USA
[7] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA
[8] Univ Michigan, Dept Ophthalmol, Ann Arbor, MI 48109 USA
[9] Harvard Univ, Sch Med, Charlestown, MA 02129 USA
[10] Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA
[11] Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China
[12] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA
[13] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA
[14] Max Planck Inst Biochem, Dept Cell Biol, D-82152 Martinsried, Germany
[15] Peking Univ, Sch Oncol, Beijing Inst Canc Res, Dept Biochem & Mol Biol, Beijing 100036, Peoples R China
[16] Univ Calif San Diego, Sch Med, Dept Pharmacol & Neurosci, La Jolla, CA 92093 USA
[17] Univ Cologne, Dept Pediat, D-5000 Cologne 41, Germany
[18] Univ Zurich, Dept Pediat, CH-8006 Zurich, Switzerland
[19] Univ Washington, Dept Pediat, Seattle, WA 98105 USA
[20] Hannover Med Sch, Inst Mol Biol, D-30625 Hannover, Germany
[21] Univ Cologne, Inst Genet, D-5000 Cologne 41, Germany
[22] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
关键词
D O I
10.1038/ng1786
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The molecular basis of nephronophthisis(1), 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(2) 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.
引用
收藏
页码:674 / 681
页数:8
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