Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers.
Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers.
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DOI：
10.1186/1471-2156-13-23
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发表时间：
2012-03-31
期刊：
影响因子：
2.9
通讯作者：
Matsuo M
中科院分区：
文献类型：
--
作者：
Malueka RG;Takaoka Y;Yagi M;Awano H;Lee T;Dwianingsih EK;Nishida A;Takeshima Y;Matsuo M
杜氏肌营养不良症是一种致命的肌肉萎缩疾病，其特征是由肌营养不良蛋白基因突变引起的肌营养不良蛋白缺乏。在与反义寡核苷酸剪接过程中跳过目标肌营养不良蛋白外显子作为在 DMD 中表达肌营养不良蛋白的最合理方式而引起了广泛关注。反义寡核苷酸是针对剪接调节序列（例如靶外显子的剪接增强子序列）而设计的。最近，我们报道了一种化学激酶抑制剂特异性增强突变肌营养不良蛋白外显子31的跳跃，表明外显子特异性剪接调节系统的存在。然而，此类个体监管体系的基础很大程度上未知。在这里，我们根据剪接调节因子对肌营养不良蛋白外显子进行了分类。使用基于计算机的机器学习系统，我们首先使用 25 个剪接调节因子索引作为决策标记，构建了一个决策树，将 77 个真实外显子与 14 个已知神秘外显子分开。我们评估了本研究中确定的新型神秘外显子（外显子 11a）的分类准确性。然而，该树将外显子 11a 错误标记为真正的外显子。因此，我们重新构建了决策树来分离所有 15 个神秘外显子。修订后的决策树将 77 个真实外显子分为五组。此外，所有九个与疾病相关的新外显子都被成功分类为外显子，验证了决策树。其中一组由 30 个外显子组成，其特点是高密度的外显子剪接增强子序列。这表明靶向剪接增强子序列的 AO 将有效诱导属于该组的外显子的跳跃。决策树将 77 个真实外显子分为五组。我们的分类可能有助于建立杜氏肌营养不良症的外显子跳跃治疗策略。
Duchenne muscular dystrophy, a fatal muscle-wasting disease, is characterized by dystrophin deficiency caused by mutations in the dystrophin gene. Skipping of a target dystrophin exon during splicing with antisense oligonucleotides is attracting much attention as the most plausible way to express dystrophin in DMD. Antisense oligonucleotides have been designed against splicing regulatory sequences such as splicing enhancer sequences of target exons. Recently, we reported that a chemical kinase inhibitor specifically enhances the skipping of mutated dystrophin exon 31, indicating the existence of exon-specific splicing regulatory systems. However, the basis for such individual regulatory systems is largely unknown. Here, we categorized the dystrophin exons in terms of their splicing regulatory factors. Using a computer-based machine learning system, we first constructed a decision tree separating 77 authentic from 14 known cryptic exons using 25 indexes of splicing regulatory factors as decision markers. We evaluated the classification accuracy of a novel cryptic exon (exon 11a) identified in this study. However, the tree mislabeled exon 11a as a true exon. Therefore, we re-constructed the decision tree to separate all 15 cryptic exons. The revised decision tree categorized the 77 authentic exons into five groups. Furthermore, all nine disease-associated novel exons were successfully categorized as exons, validating the decision tree. One group, consisting of 30 exons, was characterized by a high density of exonic splicing enhancer sequences. This suggests that AOs targeting splicing enhancer sequences would efficiently induce skipping of exons belonging to this group. The decision tree categorized the 77 authentic exons into five groups. Our classification may help to establish the strategy for exon skipping therapy for Duchenne muscular dystrophy.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
15.9
作者：
Shiga, N;Takeshima, Y;Matsuo, M
通讯作者：
Matsuo, M
影响因子：
14.9
作者：
SHAPIRO, MB;SENAPATHY, P
通讯作者：
SENAPATHY, P
影响因子：
15.9
作者：
NISHIO, H;TAKESHIMA, Y;MATSUO, M
通讯作者：
MATSUO, M
影响因子：
46.9
作者：
Kingsford, Carl;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.