Li Wei
Medical College, Shantou University, Shantou City, Guangdong Province, China.
PLoS One. 2017 Jun 1;12(6):e0178519. doi: 10.1371/journal.pone.0178519. eCollection 2017.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (∼95% of SMA cases) or mutation (∼5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are described in this article. Of extraordinary interest, the structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136) with SMA-linked missense mutations, which cause disruptions of electrostatic interactions for Asp44, Glu134 and Gln136, and result in three functionally deficient SMA-linked SMN mutants, Asp44Val, Glu134Lys and Gln136Glu. From the computational analysis, it is also possible that SMN's Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，其脊髓前角的α运动神经元功能失调。SMA是由生存运动神经元1基因SMN1的缺失（约95%的SMA病例）或突变（约5%的SMA病例）引起的。作为SMN1的产物，SMN是SMN复合体的一个组成部分，还参与小核核糖核蛋白（snRNP）的生物合成，而snRNP在SMA发病机制的前体mRNA剪接中起关键作用。为了研究SMN1的SMA相关突变如何导致SMN的结构/功能缺陷，本文进行并描述了一系列与SMN相关结构的计算分析。特别值得关注的是，结构分析突出了三个带有SMA相关错义突变的SMN残基（Asp44、Glu134和Gln136），这些突变导致Asp44、Glu134和Gln136的静电相互作用中断，并产生了三个功能缺陷的SMA相关SMN突变体，即Asp44Val、Glu134Lys和Gln136Glu。从计算分析中还可以看出，SMN的Lys45和Asp36可能在SMN-Gemin2复合体结构界面处充当两个静电夹子。
