Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Clin Genet. 2013 Aug;84(2):142-9. doi: 10.1111/cge.12181. Epub 2013 Jun 5.
Alternative splicing is highly regulated in tissue-specific and development-specific patterns, and it has been estimated that 15% of disease-causing point mutations affect pre-mRNA splicing. In this review, we consider the cis-acting splice site and trans-acting splicing factor mutations that affect pre-mRNA splicing and contribute to retinal degeneration. Numerous splice site mutations have been identified in retinitis pigmentosa (RP) and various cone-rod dystrophies. Mutations in alternatively spliced retina-specific exons of the widely expressed RPGR and COL2A1 genes lead primarily to X-linked RP and ocular variants of Stickler syndrome, respectively. Furthermore, mutations in general pre-mRNA splicing factors, such as PRPF31, PRPF8, and PRPF3, predominantly cause autosomal dominant RP. These findings suggest an important role for pre-mRNA splicing in retinal homeostasis and the pathogenesis of retinal degenerative diseases. The development of novel therapeutic strategies to modulate aberrant splicing, including small molecule-based therapies, has the potential to lead to new treatments for retinal degenerative diseases.
可变剪接在组织特异性和发育特异性模式中受到高度调控，据估计，15%的致病点突变影响前体 mRNA 的剪接。在这篇综述中，我们考虑了影响前体 mRNA 剪接并导致视网膜变性的顺式作用剪接位点和反式作用剪接因子突变。许多剪接位点突变已在色素性视网膜炎 (RP) 和各种锥杆营养不良中被发现。广泛表达的 RPGR 和 COL2A1 基因中视网膜特异性外显子的可变剪接突变主要导致 X 连锁 RP 和 Stickler 综合征的眼部变异。此外，一般前体 mRNA 剪接因子（如 PRPF31、PRPF8 和 PRPF3）的突变主要导致常染色体显性 RP。这些发现表明前体 mRNA 剪接在视网膜稳态和视网膜退行性疾病发病机制中的重要作用。开发调节异常剪接的新型治疗策略，包括基于小分子的疗法，有可能为视网膜退行性疾病带来新的治疗方法。
