Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons
Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons
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DOI：
10.1073/pnas.0704140104
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发表时间：
2007-10-02
影响因子：
11.1
通讯作者：
Martens, Jeffrey R.
中科院分区：
文献类型：
--
作者：
McEwen, Dyke P.;Koenekoop, Robert K.;Martens, Jeffrey R.
纤毛调节多种功能，例如运动性、液体平衡和感官知觉。嗅觉感觉神经元（OSN）的纤毛区室化气味检测所需的信号蛋白，然而，关于蛋白质分选/进入嗅觉纤毛的机制知之甚少。肾囊蛋白是纤毛蛋白的一个家族，可能在从基体到纤毛轴丝的运输过程中参与货物分选。在人类中，纤毛-中心体蛋白CEP 290/NPHP 6的功能丧失与Joubert和Meckel综合征相关，而亚型突变导致Leber先天性黑蒙（LCA），一种早发性视网膜营养不良。在这里，我们报告说，CEP 290-LCA患者表现出严重异常的嗅觉功能。在CEP 290 [视网膜营养不良-16小鼠（rd 16）]中具有亚型突变的小鼠模型中，嗅觉电图记录显示与CEP 290-LCA患者类似的嗅觉缺失表型。尽管嗅觉功能丧失，但在rd 16小鼠中OSN的纤毛保持完整。与野生型一样，CEP 290定位于rd 16 OSN的树突状突起，在那里它与纤毛转运蛋白和嗅觉G蛋白G（olf）和G（gamma 13）复合。有趣的是，我们观察到G（olf）和G（gamma 13）的纤毛定位缺陷，但没有G蛋白偶联的气味受体或其他成分的气味信号通路中的rd 16 OSN。我们的数据牵连不同的机制纤毛运输的嗅觉信号蛋白，CEP 290是一个关键的调解人参与G蛋白的运输。嗅觉功能的评估，因此，可以作为一个有用的诊断工具，遗传筛查某些综合征睫状体疾病。
Cilia regulate diverse functions such as motility, fluid balance, and sensory perception. The cilia of olfactory sensory neurons (OSNs) compartmentalize the signaling proteins necessary for odor detection; however, little is known regarding the mechanisms of protein sorting/entry into olfactory cilia. Nephrocystins are a family of ciliary proteins likely involved in cargo sorting during transport from the basal body to the ciliary axoneme. In humans, loss-of-function of the cilia-centrosomal protein CEP290/NPHP6 is associated with Joubert and Meckel syndromes, whereas hypomorphic mutations result in Leber congenital amaurosis (LCA), a form of early-onset retinal dystrophy. Here, we report that CEP290-LCA patients exhibit severely abnormal olfactory function. In a mouse model with hypomorphic mutations in CEP290 [retinal dystrophy-16 mice (rd16)], electro-olfactogram recordings revealed an anosmic phenotype analogous to that of CEP290-LCA patients. Despite the loss of olfactory function, cilia of OSNs remained intact in the rd16 mice. As in wild type, CEP290 localized to dendritic knobs of rd16 OSNs, where it was in complex with ciliary transport proteins and the olfactory G proteins G(olf) and G(gamma 13). Interestingly, we observed defective ciliary localization of G(olf) and G(gamma 13) but not of G protein-coupled odorant receptors or other components of the odorant signaling pathway in the rd16 OSNs. Our data implicate distinct mechanisms for ciliary transport of olfactory signaling proteins, with CEP290 being a key mediator involved in G protein trafficking. The assessment of olfactory function can, therefore, serve as a useful diagnostic tool for genetic screening of certain syndromic ciliary diseases.