Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients
Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients
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DOI：
10.1093/hmg/10.24.2841
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发表时间：
2001-11-15
影响因子：
3.5
通讯作者：
Burghes, AHM
中科院分区：
文献类型：
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作者：
Andreassi, C;Jarecki, J;Burghes, AHM
近端脊髓性肌萎缩症（SMA）是由运动神经元基因SMN1端粒存活突变引起的一种常见的运动神经元疾病。所有SMA患者均保留运动神经元SMN2基因的着丝体存活，但不能产生足够的SMN蛋白来预防临床症状的发展。SMN1和SMN2基因在功能上的不同是由于单个核苷酸的变化。这种变化影响了外显子7被整合到mRNA转录物中的效率。因此，SMN2比SMN1产生更少的全长mRNA和蛋白质。我们已经筛选了一个化合物库，以确定可以改变SMN2基因剪接模式的化合物。在这里，我们报道了化合物aclarubicin增加了SMN2转录本中外显子7的保留。我们发现，阿克鲁比星有效地诱导外显子7掺入I型SMA成纤维细胞内源性基因的SMN2转录本，以及运动神经元细胞系NSC34的SMN2小基因转录本。在I型成纤维细胞中，治疗导致SMN蛋白和宝石增加到正常水平。我们的研究结果表明，剪接模式的改变代表了疾病治疗中基因表达修饰的新途径，并证明了高通量筛选检测影响基因剪接模式的化合物的可行性。
Proximal spinal muscular atrophy (SMA) is a common motor neuron disorder caused by mutation of the telomeric survival of motor neuron gene SMN1. The centromeric survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. The SMN1 and SMN2 genes differ functionally by a single nucleotide change. This change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. Thus, SMN2 produces less full-length mRNA and protein than SMN1. We have screened a library of compounds in order to identify ones that can alter the splicing pattern of the SMN2 gene. Here, we report that the compound aclarubicin increases the retention of exon 7 into the SMN2 transcript. We show that aclarubicin effectively induces incorporation of exon 7 into SMN2 transcripts from the endogenous gene in type I SMA fibroblasts as well as into transcripts from a SMN2 minigene in the motor neuron cell line NSC34. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. Our results suggest that alteration of splicing pattern represents a new approach to modification of gene expression in disease treatment and demonstrate the feasibility of high throughput screens to detect compounds that affect the splicing pattern of a gene.