RPGR: Its role in photoreceptor physiology, human disease, and future therapies.
RPGR: Its role in photoreceptor physiology, human disease, and future therapies.
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DOI：
10.1016/j.exer.2015.06.007
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发表时间：
2015-09
影响因子：
3.4
通讯作者：
Wright AF
中科院分区：
文献类型：
--
作者：
Megaw RD;Soares DC;Wright AF
哺乳动物的光感受器含有专门的连接纤毛，其将内节（IS）连接到外节（OS）。由于睫状蛋白的突变导致的连接纤毛的功能障碍是遗传性视网膜营养不良性视网膜色素变性（RP）的常见原因。影响视网膜色素变性GTGR调节蛋白（RPGR）的突变是其中一个原因，影响10-20%的RP患者和大多数X连锁RP患者。RPGR位于连接纤毛的光感受器中。它与多种纤毛蛋白相互作用，但其确切功能尚不清楚。最近，在我们对RPGR功能的理解和治疗方法的开发方面都取得了重要进展。这篇综述总结了现有的人类RPGR功能和功能障碍的文献，并建议，RPGR发挥的作用，在睫状门的功能，控制膜和可溶性蛋白质的光感受器外段的访问。我们讨论了用于研究和治疗RPGR疾病的关键模型，并建议基因增强治疗提供了一个现实的治疗方法，虽然重要的问题仍然有待回答，而基于视网膜祖细胞的细胞替代治疗代表了一个更遥远的前景。我们讨论了RPGR蛋白在光感受器维持中的拟议功能。我们重点介绍了该领域用于研究Rpgr的动物模型。我们讨论了基因治疗的最新进展，作为一种可能的治疗RPGR突变。
Mammalian photoreceptors contain specialised connecting cilia that connect the inner (IS) to the outer segments (OS). Dysfunction of the connecting cilia due to mutations in ciliary proteins are a common cause of the inherited retinal dystrophy retinitis pigmentosa (RP). Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) protein is one such cause, affecting 10–20% of all people with RP and the majority of those with X-linked RP. RPGR is located in photoreceptor connecting cilia. It interacts with a wide variety of ciliary proteins, but its exact function is unknown. Recently, there have been important advances both in our understanding of RPGR function and towards the development of a therapy. This review summarises the existing literature on human RPGR function and dysfunction, and suggests that RPGR plays a role in the function of the ciliary gate, which controls access of both membrane and soluble proteins to the photoreceptor outer segment. We discuss key models used to investigate and treat RPGR disease and suggest that gene augmentation therapy offers a realistic therapeutic approach, although important questions still remain to be answered, while cell replacement therapy based on retinal progenitor cells represents a more distant prospect. We discuss the proposed function(s) of the RPGR protein in photoreceptor maintenance. We highlight the animal models used in the field to research Rpgr. We discuss recent advances in gene therapy as a possible treatment for RPGR mutations.