Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2β
Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2β
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DOI：
10.1074/jbc.m301800200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Wu, JY
中科院分区：
文献类型：
--
作者：
Jiang, ZH;Tang, H;Wu, JY
在FTDP-17（一种常染色体显性遗传性神经退行性疾病）中发现了导致异常剪接的人类tau基因突变。这些突变导致tau异常剪接的分子机制尚不清楚。我们在tau基因的第10外显子N279K和Del280K上发现了两个突变。结果表明外显子剪接增强子位于外显子10。这种富含ag的剪接增强子的活性被N279K和Del280K突变改变。该外显子增强子元件与人tra2 β蛋白相互作用。Tra2beta与外显子剪接增强子之间的相互作用与该增强子元件刺激剪接的活性相关。生化研究，包括转染细胞的体外剪接和RNA干扰实验，支持tra2 β蛋白在调节人类tau基因的选择性剪接中的作用。我们的研究结果表明，人类tau基因是选择性剪接调节因子Tra2beta的靶基因，这表明Tra2beta可能在异常的tau外显子10选择性剪接和tau病的发病机制中发挥作用。
Mutations in the human tau gene leading to aberrant splicing have been identified in FTDP-17, an autosomal dominant hereditary neurodegenerative disorder. Molecular mechanisms by which such mutations cause tau aberrant splicing were not understood. We characterized two mutations in exon 10 of the tau gene, N279K and Del280K. Our results revealed an exonic splicing enhancer element located in exon 10. The activity of this AG-rich splicing enhancer was altered by N279K and Del280K mutations. This exonic enhancer element interacts with human Tra2beta protein. The interaction between Tra2beta and the exonic splicing enhancer correlates with the activity of this enhancer element in stimulating splicing. Biochemical studies including in vitro splicing and RNA interference experiments in transfected cells support a role for Tra2beta protein in regulating alternative splicing of human tau gene. Our results implicate the human tau gene as a target gene for the alternative splicing regulator Tra2beta, suggesting that Tra2beta may play a role in aberrant tau exon 10 alternative splicing and in the pathogenesis of tauopathies.