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
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nat Genet. 2006 Jun;38(6):674-81. doi: 10.1038/ng1786. Epub 2006 May 7.
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.
肾单位肾痨是儿童和青年肾衰竭最常见的遗传病因，但其分子基础以及与Joubert综合征中视网膜变性和小脑蚓部发育不全的关联尚不清楚。通过定位克隆，我们在此鉴定出CEP290基因中的突变可导致肾单位肾痨。它编码一种含有多个结构域的蛋白质，这些结构域也存在于参与染色体分离的蛋白质CENPF中。CEP290（也称为NPHP6）与ATF4相互作用并调节其活性，ATF4是一种与cAMP依赖性肾囊肿形成有关的转录因子。NPHP6以细胞周期依赖性方式存在于肾上皮细胞的中心体和细胞核中以及光感受器的连接纤毛中。在斑马鱼中消除其功能可重现Joubert综合征的肾脏、视网膜和小脑表型。我们的研究结果有助于在多囊肾病、视网膜变性和中枢神经系统发育的发病机制中建立中心体功能、组织结构和转录调控之间的联系。
