Singh Ravindra N, Singh Natalia N
Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.
Adv Neurobiol. 2018;20:31-61. doi: 10.1007/978-3-319-89689-2_2.
Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.
脊髓性肌萎缩症（SMA）是与婴儿死亡率相关的主要遗传疾病之一。超过90%的SMA病例是由生存运动神经元1（SMN1）基因的缺失或突变引起的。SMN2是SMN1的一个几乎相同的拷贝，由于外显子7的主要跳跃，它不能补偿SMN1的缺失。然而，已证明校正SMN2外显子7的剪接对SMA患者具有治疗益处。唯一被批准用于SMA的药物是一种反义寡核苷酸（Spinraza™/Nusinersen），它通过阻断位于外显子7下游紧邻的内含子剪接沉默子N1（ISS-N1）来校正SMN2外显子7的剪接。ISS-N1是一个复杂的调控元件，包含重叠的负性基序并隔离一个隐蔽剪接位点。超过40种蛋白质因子参与了SMN外显子7剪接的调控。有证据支持在氧化应激期间SMN的多个外显子会发生可变剪接，氧化应激与越来越多的病理状况相关。在此，我们提供了关于SMN基因剪接调控机制的最新阐述。
