Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
Neurosci Lett. 2012 Sep 6;525(1):72-5. doi: 10.1016/j.neulet.2012.07.024. Epub 2012 Jul 20.
Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and caused by the loss of functional Survival Motor Neuron 1 (SMN1). The remaining copy gene, SMN2, is unable to rescue from disease because the primary gene product lacks the final coding exon, exon 7, due to an alternative splicing event. While SMNΔ7 is a rapidly degraded protein, exon 7 is not specifically required in a sequence-specific manner to confer increased functionality to this truncated protein. Based upon this molecular observation, aminoglycosides have been examined to artificially elongate the C-terminus of SMNΔ7 by "read-through" of the stop codon. An SMNΔ7 read-through event benefits intermediate mouse models of SMA. Here we demonstrate that delivery of a read-through inducing compound directly to the CNS can partially lessen the severity of a severe model of SMA (Smn(-/-); SMN2(+/+)), albeit not to the extent seen in the less severe model. This further demonstrates the utility of read-through inducing compounds in SMA.
脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因，是由功能性运动神经元生存 1 号（SMN1）缺失引起的。由于剪接事件，另一个主要基因 SMN2 无法产生具有功能的产物，因为主要基因产物缺乏最后一个编码外显子 7。虽然 SMNΔ7 是一种快速降解的蛋白质，但外显子 7 并不需要以特定的序列特异性方式来赋予这种截短蛋白增加的功能。基于这一分子观察结果，已研究了氨基糖苷类药物通过“通读”终止密码子来人为延长 SMNΔ7 的 C 末端。SMNΔ7 通读事件有益于中间型 SMA 小鼠模型。在这里，我们证明了将通读诱导化合物直接递送到中枢神经系统可以部分减轻严重型 SMA 模型（Smn(-/-); SMN2(+/+))的严重程度，尽管不如在较轻的模型中看到的那么明显。这进一步证明了通读诱导化合物在 SMA 中的实用性。
