Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Genetica. 2022 Oct;150(5):289-297. doi: 10.1007/s10709-022-00161-x. Epub 2022 Aug 1.
Although predicting the effects of variants near intron-exon boundaries is relatively straightforward, predicting the functional Exon Splicing Enhancers (ESEs) and the possible effects of variants within ESEs remains a challenge. Considering the essential role of CYP2D6/CYP2C19 genes in drug metabolism, we attempted to identify variants that are most likely to disrupt splicing through their effect on these ESEs. ESEs were predicted in these two genes using ESEfinder 3.0, incorporating a series of filters (increased threshold and evolutionary conservation). Finally, reported mutations were evaluated for their potential to disrupt splicing by affecting these ESEs. Initially, 169 and 243 ESEs were predicted for CYP2C19/CYP2D6, respectively. However, applying the filters, the number of predicted ESEs was reduced to 26 and 19 in CYP2C19/CYP2D6, respectively. Comparing prioritized predicted ESEs with known sequence variants in CYP2C19/CYP2D6 genes highlights 18 variations within conserved ESEs for each gene. We found good agreement in cases where such predictions could be compared to experimental evidence. In total, we prioritized a subset of mutational changes in CYP2C19/CYP2D6 genes that may affect the function of these genes and lead to altered drug responses. Clinical studies and functional analysis for investigating detailed functional consequences of the mentioned mutations and their phenotypic outcomes is mostly recommended.
虽然预测内含子-外显子边界附近变体的影响相对简单，但预测功能性外显子剪接增强子（ESE）以及 ESE 内变体的可能影响仍然是一个挑战。鉴于 CYP2D6/CYP2C19 基因在药物代谢中的重要作用，我们试图确定最有可能通过影响这些 ESE 而导致剪接中断的变体。使用 ESEfinder 3.0 预测这两个基因中的 ESE，同时采用了一系列筛选器（增加阈值和进化保守性）。最后，通过评估这些突变是否通过影响这些 ESE 来破坏剪接，从而评估它们潜在的影响。最初，分别预测 CYP2C19/CYP2D6 中有 169 个和 243 个 ESE。然而，应用筛选器后，分别将 CYP2C19/CYP2D6 中的预测 ESE 数量减少到 26 个和 19 个。将优先预测的 ESE 与 CYP2C19/CYP2D6 基因中的已知序列变异进行比较，突出了每个基因中保守 ESE 内的 18 个变异。在可以与实验证据进行比较的情况下，我们发现这些预测具有很好的一致性。总的来说，我们优先考虑 CYP2C19/CYP2D6 基因中可能影响这些基因功能并导致药物反应改变的突变变化子集。建议进行临床研究和功能分析，以研究所提到的突变及其表型结果的详细功能后果。
