An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN
An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN
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DOI：
10.1093/hmg/9.2.259
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发表时间：
2000-01-22
影响因子：
3.5
通讯作者：
Androphy, EJ
中科院分区：
文献类型：
--
作者：
Lorson, CL;Androphy, EJ
运动神经元存活基因SMN 1和SMN 2编码相同的蛋白质;然而，只有SMN 1的纯合缺失与脊髓性肌萎缩症（SMA）的发生相关。我们以前已经表明，一个单一的非多态性核苷酸差异SMN外显子7显着影响SMN mRNA的加工。SMN 1主要产生全长RNA，而SMN 2表达显著减少的全长RNA和丰富水平的缺乏外显子7的异常剪接转录物，通过鉴定外显子7附近剪接位点内的几个突变，强调了正确外显子7加工的重要性，在这里，我们发现SMN外显子7中心的富含AG的外显子剪接增强子（ESE）是外显子7包含所必需的，该区域在异源环境中起ESE的作用，支持果蝇双性基因的有效体外剪接。最后，由外显子跳跃事件编码的蛋白Delta 7比全长SMN更不稳定，这为SMN 2无法补偿SMN 1的损失并导致SMA的发展提供了额外的证据。
The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homozygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7, The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7, Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7, This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, Delta 7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.