Table_2_Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond.DOCX

Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium that eventually results in blindness. Mutations in pre-mRNA processing factors (PRPF3, 4, 6, 8, 31, SNRNP200, and RP9) have been linked to 15–20% of autosomal dominant RP (adRP) cases. Current evidence indicates that PRPF mutations cause retinal specific global spliceosome dysregulation, leading to mis-splicing of numerous genes that are involved in a variety of retina-specific functions and/or general biological processes, including phototransduction, retinol metabolism, photoreceptor disk morphogenesis, retinal cell polarity, ciliogenesis, cytoskeleton and tight junction organization, waste disposal, inflammation, and apoptosis. Importantly, additional PRPF functions beyond RNA splicing have been documented recently, suggesting a more complex mechanism underlying PRPF-RPs driven disease pathogenesis. The current review focuses on the key RP-PRPF genes, depicting the current understanding of their roles in RNA splicing, impact of their mutations on retinal cell’s transcriptome and phenome, discussed in the context of model species including yeast, zebrafish, and mice. Importantly, information on PRPF functions beyond RNA splicing are discussed, aiming at a holistic investigation of PRPF-RP pathogenesis. Finally, work performed in human patient-specific lab models and developing gene and cell-based replacement therapies for the treatment of PRPF-RPs are thoroughly discussed to allow the reader to get a deeper understanding of the disease mechanisms, which we believe will facilitate the establishment of novel and better therapeutic strategies for PRPF-RP patients.

色素性视网膜炎（Retinitis Pigmentosa, RP）是最常见的遗传性视网膜疾病，以光感受器和/或视网膜色素上皮的进行性退变为特征，最终可导致失明。前mRNA加工因子（pre-mRNA processing factors，PRPF3、4、6、8、31、SNRNP200及RP9）的突变已被证实与15%~20%的常染色体显性遗传性色素性视网膜炎（autosomal dominant RP, adRP）病例相关。现有研究证据表明，PRPF突变会引发视网膜特异性的整体剪接体（spliceosome）失调，进而导致众多基因的剪接异常；这些基因参与多种视网膜特异性功能及一般生物学过程，包括光转导、视黄醇代谢、光感受器盘膜形态发生、视网膜细胞极性、纤毛发生、细胞骨架与紧密连接组织、废物清除、炎症反应及细胞凋亡。值得注意的是，近期研究已证实PRPF还存在RNA剪接以外的其他功能，这提示PRPF相关RP的疾病发病机制更为复杂。本综述聚焦于关键的RP相关PRPF基因，阐述当前学界对其在RNA剪接中作用的认知，以及其突变对视网膜细胞转录组（transcriptome）与表型组（phenome）的影响，相关讨论以酵母、斑马鱼及小鼠等模式生物为展开背景。此外，本文还探讨了PRPF在RNA剪接之外的功能，以期全面解析PRPF相关RP的发病机制。最后，本文详细讨论了基于人类患者特异性实验室模型的相关研究，以及用于治疗PRPF相关RP的基因与细胞替代疗法的开发进展，旨在帮助读者更深入地理解该疾病的发病机制，我们相信这将有助于为PRPF-RP患者建立更优质的新型治疗策略。