In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse
In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse
复制标题
新型中心体/纤毛蛋白 CEP290/NPHP6 的框内缺失扰乱了其与 RPGR 的相互作用，并导致 rd16 小鼠早发性视网膜变性。
DOI：
10.1093/hmg/ddl107
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Swaroop, Anand
中科院分区：
文献类型：
--
作者：
Chang, Bo;Khanna, Hemant;Swaroop, Anand
中心体和纤毛相关的蛋白质在建立极性和调节有丝分裂后细胞的细胞内转运方面起着至关重要的作用。使用遗传学映射和位置候选策略，我们确定了新型的中心蛋白CEP290（也称为NPHP6）中的框架缺失，导致新鉴定的小鼠突变体RD16中导致早发性视网膜变性。我们证明，CEP290主要定位于分裂细胞的中心体和视网膜感受器的纤毛。我们表明，在视网膜中，CEP290与包括RPGR在内的几种基于微管的转运蛋白相关联，该蛋白在大约15％的色素性视网膜炎患者中突变。在RD16视网膜中检测到截短的CEP290蛋白（deltacep290），但量大大减少。但是，突变蛋白与特定的RPGR同工型表现出更强的关联。免疫元标记研究表明，RD16视网膜的光感受器中RPGR和光转传蛋白的重新分布。我们的发现表明，CEP290在睫状运输中的关键功能，并提供了对早期感受感受器变性机制的见解。
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.