An intronic element contributes to splicing repression in spinal muscular atrophy
An intronic element contributes to splicing repression in spinal muscular atrophy
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DOI：
10.1073/pnas.0700343104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Manley, James L.
中科院分区：
文献类型：
--
作者：
Kashima, Tsuyoshi;Rao, Nishta;Manley, James L.
神经退行性疾病脊肌萎缩症是由存活运动神经元1(SMN1)基因突变引起的。SMN2是SMN1的一个几乎相同的拷贝，无法预防疾病，因为大多数SMN2转录产物缺乏外显子7，因此产生了一种无功能的蛋白质。SMN 2外显子7剪接效率低下的一个关键原因是外显子7内SMN1和SMN 2之间的单核苷酸差异。我们先前提供的证据表明，这种碱基变化通过产生一个抑制元件--异质性核核糖核蛋白(HnRNP)依赖的外显子剪接沉默来抑制外显子7的剪接。我们现在发现，SMN1和SMN2之间另一个罕见的核苷酸差异，在内含子7，可能创建了第二个SMN2特异的hnRNP Al结合位点。值得注意的是，这种单一的碱基变化确实产生了一个高密度的hnRNP ALL结合位点，而破坏它的碱基替换在体内恢复了外显子7的包涵体，并在体外阻止了hnRNP A1的结合。我们认为，通过与外显子和内含子结合的hnRNP A1分子之间的相互作用来排除外显子7，并讨论了这种排除在SMN表达和更广泛的剪接控制方面的意义。
The neurodegenerative disease spinal muscular atrophy is caused by mutation of the survival motor neuron 1 (SMN1) gene. SMN2 is a nearly identical copy of SMN1 that is unable to prevent disease, because most SMN2 transcripts lack exon 7 and thus produce a nonfunctional protein. A key cause of inefficient SMN2 exon 7 splicing is a single nucleotide difference between SMN1 and SMN2 within exon 7. We previously provided evidence that this base change suppresses exon 7 splicing by creating an inhibitory element, a heterogeneous nuclear ribonucleoprotein (hnRNP) Aldependent exonic splicing silencer. We now find that another rare nucleoticle difference between SMN1 and SMN2, in intron 7, potentially creates a second SMN2-specific hnRNP Al binding site. Remarkably, this single base change does indeed create a highaffinity hnRNP All binding site, and base substitutions that disrupt it restore exon 7 inclusion in vivo and prevent hnRNP A1 binding in vitro. We propose that interactions between hnRNP A1 molecules bound to the exonic and intronic sites cooperate to exclude exon 7 and discuss the significance of this exclusion with respect to SMN expression and splicing control more generally.