PLoS One. 2017 Jun 1;12(6):e0178519. doi: 10.1371/journal.pone.0178519. 

How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein?

Li W.

Department of Pharmacology, Shantou University Medical College, Shantou City, Guangdong Province, China

Correspondence should be addressed to

Wei Li


Department of Pharmacology, Shantou University Medical College, Shantou City, Guangdong Province, China



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, the SMN protein is a key component of the SMN complex, and also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing during 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 presented here in this article. Of extraordinary interest, the computational structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136) with SMA-linked missense mutations, which cause local 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 structural analysis, it appears also possible that SMN’s Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface, structurally stabilizing the SMN-Gemin2 complex. Moreover, the structural analysis of a group of four further SMA-linked mutations (Trp92Ser, Trp102X, Ala111Gly and Ile116Phe) highlight the potential significance of the deeply buried hydrophobic side chains of Trp92, Trp102, Ala111 and Ile116 in the SMN Tudor domain, the essential part of SMN for its ability to bind the Sm proteins of snRNPs.



While experimentally determined biological molecular structures keeps being deposited in the Protein Data Bank (PDB), it becomes possible to analyze and illustrate the structural consequence(s) (Figure 1) of clinically identified genetic mutations, which will be helpful for a more insightful understanding of the molecular pathogenesis of genetic diseases (such as SMA) from a structural point of view, and how gene editing technologies actually work (that is, in case they do work from bench to bedside) to treat genetic diseases through correction(s) at the DNA level in an inheritable manner.



Figure 1. A flowchart for the analysis of structural/functional consequence(s) of clinically identified diseases-linked genetic mutations. In this article, the SMA disease was shown as one example of the computational analysis based on experimentally determined structures of SMN, the SMA protein.



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