Chang Bo, Khanna Hemant, Hawes Norman, Jimeno David, He Shirley, Lillo Concepcion, Parapuram Sunil K, Cheng Hong, Scott Alison, Hurd Ron E, Sayer John A, Otto Edgar A, Attanasio Massimo, O'Toole John F, Jin Genglin, Shou Chengchao, Hildebrandt Friedhelm, Williams David S, Heckenlively John R, Swaroop Anand
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Hum Mol Genet. 2006 Jun 1;15(11):1847-57. doi: 10.1093/hmg/ddl107. Epub 2006 Apr 21.
Centrosome- and cilia-associated proteins play crucial roles in establishing polarity and regulating intracellular transport in post-mitotic cells. Using genetic mapping and positional candidate strategy, we have identified an in-frame deletion in a novel centrosomal protein CEP290 (also called NPHP6), leading to early-onset retinal degeneration in a newly identified mouse mutant, rd16. We demonstrate that CEP290 localizes primarily to centrosomes of dividing cells and to the connecting cilium of retinal photoreceptors. We show that, in the retina, CEP290 associates with several microtubule-based transport proteins including RPGR, which is mutated in approximately 15% of patients with retinitis pigmentosa. A truncated CEP290 protein (DeltaCEP290) is detected in the rd16 retina, but in considerably reduced amounts; however, the mutant protein exhibits stronger association with specific RPGR isoform(s). Immunogold labeling studies demonstrate the redistribution of RPGR and of phototransduction proteins in the photoreceptors of rd16 retina. Our findings suggest a critical function for CEP290 in ciliary transport and provide insights into the mechanism of early-onset photoreceptor degeneration.
中心体和纤毛相关蛋白在有丝分裂后细胞中建立极性和调节细胞内运输方面发挥着关键作用。利用遗传图谱和定位候选策略，我们在一种新发现的中心体蛋白CEP290（也称为NPHP6）中鉴定出一个框内缺失，该缺失导致新鉴定的小鼠突变体rd16出现早发性视网膜变性。我们证明CEP290主要定位于分裂细胞的中心体和视网膜光感受器的连接纤毛。我们表明，在视网膜中，CEP290与几种基于微管的运输蛋白相关，包括RPGR，约15%的色素性视网膜炎患者中该蛋白发生突变。在rd16视网膜中检测到截短的CEP290蛋白（DeltaCEP290），但其含量显著减少；然而，突变蛋白与特定RPGR异构体的结合更强。免疫金标记研究表明RPGR和光转导蛋白在rd16视网膜光感受器中重新分布。我们的研究结果表明CEP290在纤毛运输中具有关键功能，并为早发性光感受器变性的机制提供了见解。
