Splicing of the Survival Motor Neuron genes and implications for treatment of SMA
Splicing of the Survival Motor Neuron genes and implications for treatment of SMA
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DOI：
10.2741/3670
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发表时间：
2010-06-01
影响因子：
3.1
通讯作者：
Chandler, Dawn S.
中科院分区：
文献类型：
--
作者：
Bebee, Thomas W.;Gladman, Jordan T.;Chandler, Dawn S.
近端脊髓性肌萎缩症（SMA）是一种由运动神经元存活蛋白（SMN）水平低下引起的神经肌肉疾病。SMN水平降低是由于运动神经元生存-1（SMN 1）基因的丢失。人类携带几乎相同的SMN 2基因，由于外显子7中的C至T核苷酸改变导致外显子7的RNA剪接效率低下，因此SMN 2基因产生截短蛋白。SMN外显子7的这种排除是SMA疾病发作的核心，然而，这提供了一种独特的治疗干预，其中SMN 2基因的校正剪接将恢复SMN功能。外显子7剪接受许多外显子和内含子剪接调节序列以及结合它们的反式因子调节。对SMN前mRNA剪接方式的更好理解导致了旨在纠正SMN 2剪接的靶向治疗的开发。随着以纠正SMN 2剪接为目标的治疗方法的不断开发，可用的SMA小鼠模型可用于验证其在疾病治疗中的潜力。
Proximal spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of the survival motor neuron (SMN) protein. The reduced SMN levels are due to loss of the survival motor neuron-1 (SMN1) gene. Humans carry a nearly identical SMN2 gene that generates a truncated protein, due to a C to T nucleotide alteration in exon 7 that leads to inefficient RNA splicing of exon 7. This exclusion of SMN exon 7 is central to the onset of the SMA disease, however, this offers a unique therapeutic intervention in which corrective splicing of the SMN2 gene would restore SMN function. Exon 7 splicing is regulated by a number of exonic and intronic splicing regulatory sequences and trans-factors that bind them. A better understanding of the way SMN pre-mRNA is spliced has lead to the development of targeted therapies aimed at correcting SMN2 splicing. As therapeutics targeted toward correction of SMN2 splicing continue to be developed available SMA mouse models can be utilized in validating their potential in disease treatment.