The severe childhood disease spinal muscular atrophy (SMA) arises from the homozygous loss of the survival motor neuron 1 gene (SMN1). A homologous gene potentially encoding an identical protein, SMN2 can partially compensate for the loss of SMN1; however, the exclusion of a critical exon in the coding region during mRNA maturation results in insufficient levels of functional protein. The rate of transcription is known to influence the alternative splicing of gene transcripts, with a fast transcription rate correlating to an increase in alternative splicing. Conversely, a slower transcription rate is more likely to result in the inclusion of all exons in the transcript. Targeting SMN2 with antisense oligonucleotides to influence the processing of terminal exon 8 could be a way to slow transcription and induce the inclusion of exon 7. Interestingly, following oligomer treatment of SMA patient fibroblasts, we observed the inclusion of exon 7, as well as intron 7, in the transcript. Because the normal termination codon is located in exon 7, this exon/intron 7-SMN2 transcript should encode the normal protein and only carry a longer 3′ UTR. Further studies showed the extra 3′ UTR length contained a number of regulatory motifs that modify transcript and protein regulation, leading to translational repression of SMN. Although unlikely to provide therapeutic benefit for SMA patients, this novel technique for gene regulation could provide another avenue for the repression of undesirable gene expression in a variety of other diseases.

严重的儿童期疾病脊髓性肌萎缩症（SMA）是由存活运动神经元1基因（SMN1）的纯合缺失引起的。可能编码相同蛋白质SMN2的同源基因可以部分补偿SMN1的丢失；但是，在mRNA成熟过程中在编码区排除关键外显子会导致功能蛋白水平不足。已知转录速率会影响基因转录本的选择性剪接，而快速的转录速率与选择性剪接的增加相关。相反，较慢的转录速率更有可能导致转录本中包含所有外显子。定位到SMN2用反义寡核苷酸影响末端外显子8的加工可能是减慢转录并诱导包含外显子7的一种方法。有趣的是，在SMA患者成纤维细胞的低聚物处理后，我们观察到包含外显子7和内含子7。在笔录中。由于正常终止密码子位于外显子7中，因此该外显子/内含子7- SMN2转录本应编码正常蛋白质，并且仅携带更长的3'UTR。进一步的研究表明，额外的3'UTR长度包含许多调节转录和蛋白质调节的调节基序，从而导致SMN的翻译抑制。尽管不太可能为SMA患者提供治疗益处，但是这种用于基因调节的新技术可以为抑制多种其他疾病中不希望的基因表达提供另一条途径。