Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Germany.
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Germany.
Prog Retin Eye Res. 2021 Jan;80:100874. doi: 10.1016/j.preteyeres.2020.100874. Epub 2020 Jun 15.
Mutations which induce aberrant transcript splicing represent a distinct class of disease-causing genetic variants in retinal disease genes. Such mutations may either weaken or erase regular splice sites or create novel splice sites which alter exon recognition. While mutations affecting the canonical GU-AG dinucleotides at the splice donor and splice acceptor site are highly predictive to cause a splicing defect, other variants in the vicinity of the canonical splice sites or those affecting additional cis-acting regulatory sequences within exons or introns are much more difficult to assess or even to recognize and require additional experimental validation. Splicing mutations are unique in that the actual outcome for the transcript (e.g. exon skipping, pseudoexon inclusion, intron retention) and the encoded protein can be quite different depending on the individual mutation. In this article, we present an overview on the current knowledge about and impact of splicing mutations in inherited retinal diseases. We introduce the most common sub-classes of splicing mutations including examples from our own work and others and discuss current strategies for the identification and validation of splicing mutations, as well as therapeutic approaches, open questions, and future perspectives in this field of research.
导致异常转录剪接的突变代表了视网膜疾病基因中一类独特的致病遗传变异。这些突变可能削弱或消除常规剪接位点，或者创建改变外显子识别的新剪接位点。虽然影响剪接供体和剪接受体位点的规范 GU-AG 二核苷酸的突变极有可能导致剪接缺陷，但在规范剪接位点附近的其他变体或影响外显子或内含子内其他顺式作用调节序列的变体更难评估，甚至难以识别，需要额外的实验验证。剪接突变是独特的，因为转录本（例如外显子跳跃、假外显子包含、内含子保留）和编码蛋白的实际结果可能因个体突变而有很大差异。在本文中，我们介绍了关于遗传性视网膜疾病中剪接突变的当前知识和影响。我们介绍了最常见的剪接突变亚类，包括我们自己和其他人的工作中的例子，并讨论了目前用于鉴定和验证剪接突变的策略，以及该研究领域的治疗方法、未解决的问题和未来展望。
