Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1
Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1
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DOI：
10.1038/ng854
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发表时间：
2002-04-01
期刊：
影响因子：
30.8
通讯作者：
Krainer, AR
中科院分区：
文献类型：
--
作者：
Cartegni, L;Krainer, AR
通过外显子剪接增强子的破坏改变正确的剪接模式可能是点突变引起遗传疾病的常见机制。脊髓性肌萎缩症是由于运动神经元1基因（SMN 1）功能性存活的缺乏，尽管所有受影响的个体都携带几乎相同的正常SMN 2基因。SMN 2仅具有部分活性，因为外显子7中的沉默单核苷酸差异导致外显子跳跃。使用ESE基序预测工具，突变分析和在体内和体外剪接测定，我们表明，这种单核苷酸的变化发生在一个外显子剪接增强子的七聚体基序，这在SMN 1中是由SF 2/ASF直接识别。SF 2/ASF依赖性ESE的消除是SMN 2中外显子7无效包含的基础，导致脊髓性肌萎缩表型。
Alteration of correct splicing patterns by disruption of an exonic splicing enhancer may be a frequent mechanism by which point mutations cause genetic diseases. Spinal muscular atrophy results from the lack of functional survival of motor neuron 1 gene (SMN1), even though all affected individuals carry a nearly identical, normal SMN2 gene. SMN2 is only partially active because a translationally silent, single-nucleotide difference in exon 7 causes exon skipping. Using ESE motif-prediction tools, mutational analysis and in vivo and in vitro splicing assays, we show that this single-nucleotide change occurs within a heptamer motif of an exonic splicing enhancer, which in SMN1 is recognized directly by SF2/ASF. The abrogation of the SF2/ASF-dependent ESE is the basis for inefficient inclusion of exon 7 in SMN2, resulting in the spinal muscular atrophy phenotype.