Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1
Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1
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DOI：
10.1016/j.bbadis.2005.12.003
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发表时间：
2006-04-01
影响因子：
6.2
通讯作者：
Caillet-Boudin, ML
中科院分区：
文献类型：
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作者：
Leroy, O;Wang, JN;Caillet-Boudin, ML
选择性剪接在1型强直性肌营养不良（DM 1）中改变，DM 1是由强直性肌营养不良蛋白激酶基因的3'非翻译区中CTG三联体重复增加引起的综合征。先前，我们报道了DM1脑中Tau外显子2的优先跳跃。在这项研究中，我们分析了Tau外显子6的选择性剪接，根据所使用的3'剪接位点，Tau外显子6可以以三种不同的形式（c，p和d）插入。事实上，与对照组大脑相比，DM1大脑中外显子6c的包含减少，而6d的包含增加。DM1肌肉中未观察到外显子6剪接的改变，尽管该外显子插入正常肌肉的RNA中，并且DM1剪接改变首次在该器官中描述。与此相反，Tau mRNA的外显子2的改变在肌肉和脑中观察到。然而，含有外显子6的minigene与CELF或MBNL1 cDNA的共转染，这两个剪接因子家族被怀疑参与DM1，表明它们影响外显子6剪接。总之，这些结果显示了确定错误剪接靶向的所有外显子和器官以确定DM 1中错误剪接的失调机制的重要性。
Alternative splicing is altered in myotonic dystrophy of type 1 (DM1), a syndrome caused by an increase of CTG triplet repeats in the 3' untranslated region of the in myotonic dystrophy protein kinase gene. Previously, we reported the preferential skipping of Tau exon 2 in DM1 brains. In this study, we analyze the alternative splicing of Tau exon 6 which can be inserted in three different forms (c, p and d) depending on the 3' splice site used. In fact, inclusion of exon 6c decreases in DM1 brains compared to control brains whereas inclusion of 6d increases. Alteration of exon 6 splicing was not observed in DM1 muscle although this exon was inserted in RNAs from normal muscle and DM1 splicing alterations were first described in this organ. In contrast, alteration of exon 2 of Tau mRNA was observed in both muscle and brain. However, co-transfections of a minigene containing exon 6 with CELF or MBNL1 cDNAs, two splicing factor families suspected to be involved in DM1, showed that they influence exon 6 splicing. Altogether, these results show the importance of determining all the exons and organs targeted by mis-splicing to determine the dysregulation mechanisms of mis-splicing in DM1.