Rachel Rivka A, Yamamoto Erin A, Dewanjee Mrinal K, May-Simera Helen L, Sergeev Yuri V, Hackett Alice N, Pohida Katherine, Munasinghe Jeeva, Gotoh Norimoto, Wickstead Bill, Fariss Robert N, Dong Lijin, Li Tiansen, Swaroop Anand
National Eye Institute.
National Institute of Neurological Disease and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and.
Hum Mol Genet. 2015 Jul 1;24(13):3775-91. doi: 10.1093/hmg/ddv123. Epub 2015 Apr 9.
Distinct mutations in the centrosomal-cilia protein CEP290 lead to diverse clinical findings in syndromic ciliopathies. We show that CEP290 localizes to the transition zone in ciliated cells, precisely to the region of Y-linkers between central microtubules and plasma membrane. To create models of CEP290-associated ciliopathy syndromes, we generated Cep290(ko/ko) and Cep290(gt/gt) mice that produce no or a truncated CEP290 protein, respectively. Cep290(ko/ko) mice exhibit early vision loss and die from hydrocephalus. Retinal photoreceptors in Cep290(ko/ko) mice lack connecting cilia, and ciliated ventricular ependyma fails to mature. The minority of Cep290(ko/ko) mice that escape hydrocephalus demonstrate progressive kidney pathology. Cep290(gt/gt) mice die at mid-gestation, and the occasional Cep290(gt/gt) mouse that survives shows hydrocephalus and severely cystic kidneys. Partial loss of CEP290-interacting ciliopathy protein MKKS mitigates lethality and renal pathology in Cep290(gt/gt) mice. Our studies demonstrate domain-specific functions of CEP290 and provide novel therapeutic paradigms for ciliopathies.
中心体-纤毛蛋白CEP290中的不同突变导致综合征性纤毛病出现多样的临床症状。我们发现CEP290定位于纤毛细胞的过渡区，确切地说是定位于中央微管与质膜之间的Y形连接蛋白区域。为了构建与CEP290相关的纤毛病综合征模型，我们分别培育出不产生CEP290蛋白或产生截短型CEP290蛋白的Cep290(ko/ko)和Cep290(gt/gt)小鼠。Cep290(ko/ko)小鼠表现出早期视力丧失并死于脑积水。Cep290(ko/ko)小鼠的视网膜光感受器缺乏连接纤毛，有纤毛的脑室室管膜未能成熟。少数逃过脑积水的Cep290(ko/ko)小鼠表现出进行性肾脏病变。与CEP290相互作用的纤毛病蛋白MKKS部分缺失可减轻Cep290(gt/gt)小鼠的致死率和肾脏病变。我们的研究证明了CEP290的结构域特异性功能，并为纤毛病提供了新的治疗范例。
