Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants
Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants
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DOI：
10.1002/mgg3.840
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发表时间：
2019-06-30
影响因子：
2
通讯作者：
Kimchi-Sarfaty, Chava
中科院分区：
文献类型：
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作者：
Katneni, Upendra K.;Liss, Aaron;Kimchi-Sarfaty, Chava
背景前体mRNA剪接是一个复杂的过程，需要识别供体位点、受体位点和分支点位点与相邻的多聚嘧啶序列。剪接受剪接调节元件（SRE）的调节，SRE具有增强子和抑制子功能。位于外显子区的变体可以通过天然剪接位点、SRE和隐蔽剪接位点激活的失调来影响剪接。虽然剪接失调被认为是同义变体的主要疾病诱导机制，但其对非同义变体的疾病表型的贡献未被充分认识。方法在这项研究中，我们分析了415个致病性和120个中性F9外显子点变异，包括同义和非同义的剪接位点预测工具，SRE预测工具和体外小基因分析的影响。结果剪接位点和SRE预测工具的串联使用提供了更好的预测，但并不总是与小基因检测一致。由变体引起的剪接失调的净效应是上下文依赖性的。结论同义突变主要通过剪接调控异常引起疾病表型，但翻译速率等其他机制也起重要作用。剪接失调可能导致几种非同义变体的疾病表型。
Background Pre-mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease-inducing mechanism of synonymous variants, its contribution toward disease phenotype of non-synonymous variants is underappreciated. Methods In this study, we analyzed 415 disease-causing and 120 neutral F9 exonic point variants including both synonymous and non-synonymous for their effect on splicing using a series of in silico splice site prediction tools, SRE prediction tools, and in vitro minigene assays. Results The use of splice site and SRE prediction tools in tandem provided better prediction but were not always in agreement with the minigene assays. The net effect of splicing dysregulation caused by variants was context dependent. Minigene assays revealed that perturbed splicing can be found. Conclusion Synonymous variants primarily cause disease phenotype via splicing dysregulation while additional mechanisms such as translation rate also play an important role. Splicing dysregulation is likely to contribute to the disease phenotype of several non-synonymous variants.