Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
Weill Cornell Medical College, New York, NY 10021, USA.
Hum Mol Genet. 2018 Jun 1;27(11):2012-2024. doi: 10.1093/hmg/ddy109.
Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outersegments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography (ERG) responses by 1 month and complete outer-nuclear layer (ONL) degeneration by 2 months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outersegment (OS) proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This mouse model exhibits key features of the retinal phenotype observed in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.
纤毛内运输（IFT）是一种沿着初级纤毛和专门的感觉纤毛（如光感受器外节）发生的双向运输过程。编码各种 IFT 成分的基因与纤毛病有关。IFT172 突变导致从孤立性视网膜变性到严重综合征性纤毛病的各种疾病。在这项研究中，我们创建了一个与 IFT172 相关的视网膜变性的小鼠模型，以研究眼部疾病的机制。我们发现，杆状光感受器中 IFT172 的耗竭导致视网膜迅速退化，视网膜电图（ERG）反应在 1 个月时严重降低，外核层（ONL）在 2 个月时完全退化。我们研究了变性的分子机制，并表明 IFT172 蛋白减少导致特定光感受器外节（OS）蛋白（RHO、RP1、IFT139）的定位错误，光驱动的 alpha 转导素易位异常和神经胶质瘤相关癌基因家族成员 1（GLI1）的定位改变。这种小鼠模型表现出与 IFT172 相关失明患者观察到的视网膜表型的关键特征，可用于体内测试纤毛病疗法。
