影响剪接的外显子变异 - 导致遗传性视网膜疾病的“隐藏”突变的机会。

Exonic Variants that Affect Splicing - An Opportunity for "Hidden" Mutations Causing Inherited Retinal Diseases.

机构信息

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

出版信息

Adv Exp Med Biol. 2023;1415:183-187. doi: 10.1007/978-3-031-27681-1_27.

DOI:10.1007/978-3-031-27681-1_27

PMID:37440032

Abstract

Inherited retinal diseases (IRDs) are an extremely diverse group of ocular disorders characterized by progressive loss of photoreceptors leading to blindness. So far, pathogenic variants in over 300 genes are reported to structurally and functionally affect the retina resulting in visual impairment. Around 15% of all IRD mutations are known to affect an essential regulatory mechanism, pre-mRNA splicing, which contributes to the transcriptomic diversity. These variants disrupt potential donor and acceptor splice sites as well as other crucial cis-acting elements resulting in aberrant splicing. One group of these elements, the exonic splicing enhancers (ESEs), are involved in promoting exon definition and are likely to harbor "hidden" mutations since sequence-analyzing pipelines cannot identify them efficiently. The main focus of this review is to discuss the molecular mechanisms behind various exonic variants affecting splice sites and ESEs that lead to impaired splicing which in turn result in an IRD pathology.

摘要

遗传性视网膜疾病（IRDs）是一组极其多样化的眼部疾病，其特征是感光细胞进行性丧失，导致失明。到目前为止，据报道，超过 300 种基因的致病变体在结构和功能上影响视网膜，导致视力障碍。已知所有 IRD 突变的 15%左右会影响一个重要的调节机制，即前体 mRNA 剪接，这有助于转录组的多样性。这些变体破坏了潜在的供体和受体剪接位点以及其他关键的顺式作用元件，导致异常剪接。这些元件中的一组，即外显子剪接增强子（ESEs），参与促进外显子定义，并且可能存在“隐藏”突变，因为序列分析管道不能有效地识别它们。本篇综述的主要重点是讨论影响剪接位点和 ESEs 的各种外显子变体背后的分子机制，这些变体导致剪接受损，进而导致 IRD 病理学。