Intron 7 conserved sequence elements regulate the splicing of the SMN genes.
Intron 7 conserved sequence elements regulate the splicing of the SMN genes.
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DOI：
10.1007/s00439-009-0733-7
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发表时间：
2009-12
期刊：
影响因子：
5.3
通讯作者：
Chandler DS
中科院分区：
文献类型：
--
作者：
Gladman JT;Chandler DS
近端脊髓性肌萎缩症（SMA）是一种由存活运动神经元（SMN）蛋白水平低下引起的神经肌肉疾病。人类有两个几乎相同的SMN基因，SMN1和SMN2。SMN2基因产生一个截断蛋白，这是由于外显子7的C到T核苷酸改变，导致外显子7的RNA剪接效率低下。SMN外显子7的排除是SMA疾病发病的核心。外显子7剪接受许多外显子和内含子剪接调控序列以及结合它们的反式因子的调控。在这里，我们确定了保守的内含子序列在SMN基因。由于保守性和它们靠近外显子6到8，我们检查了5个区域。利用诱变技术确定了位于SMN基因7号内含子中影响7号外显子剪接的两个保守元件。对其中一个区域的进一步分析表明，当引入缺失或突变时，SMN转录本中外显子7的包含减少。此外，该保守区域的多聚化能够恢复正确的SMN拼接。总之，这些结果描述了一个新的内含子剪接增强子序列位于最后的内含子的SMN基因。这一发现提供了对SMN基因剪接的深入了解，使用保守的内含序列作为工具来揭示前信使RNA剪接的重要区域。更好地了解SMN前mrna的剪接方式可以导致新疗法的发展。
Proximal spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of the survival motor neuron (SMN) protein. In humans there are two nearly identical SMN genes, SMN1 and SMN2. The SMN2 gene generates a truncated protein, due to a C to T nucleotide alteration in exon 7, which leads to inefficient RNA splicing of exon 7. This exclusion of SMN exon 7 is central to the onset of the SMA disease. Exon 7 splicing is regulated by a number of exonic and intronic splicing regulatory sequences and the trans-factors that bind them. Here we identify conserved intronic sequences in the SMN genes. Five regions were examined due to conservation and their proximity to exons 6 through 8. Using mutagenesis two conserved elements located in intron 7 of the SMN genes that affect exon 7 splicing have been identified. Additional analysis of one of these regions showed decreased inclusion of exon 7 in SMN transcripts when deletions or mutations were introduced. Furthermore, multimerization of this conserved region was capable of restoring correct SMN splicing. Together these results describe a novel intronic splicing enhancer sequence located in the final intron of the SMN genes. This discovery provides insight into the splicing of the SMN genes using conserved intonic sequence as a tool to uncover regions of importance in pre-messenger RNA splicing. A better understanding of the way SMN pre-mRNA is spliced can lead to the development of new therapies.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
DOI：
10.1073/pnas.0700343104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Kashima, Tsuyoshi;Rao, Nishta;Manley, James L.
通讯作者：
Manley, James L.
影响因子：
30.8
作者：
Lefebvre, S;Burlet, P;Melki, J
通讯作者：
Melki, J
影响因子：
5.3
作者：
Singh, NK;Singh, NN;Singh, RN
通讯作者：
Singh, RN