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Article
Activation of a cryptic 5′ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene
Nucleic Acids Research
  • Natalia N. Singh, Iowa State University
  • Jose Bruno Del Rio-Malewski, Iowa State University
  • Diou Luo, Iowa State University
  • Eric W. Ottesen, Iowa State University
  • Matthew D. Howell, Iowa State University
  • Ravindra N. Singh, Iowa State University
Document Type
Article
Publication Version
Published Version
Publication Date
12-1-2017
DOI
10.1093/nar/gkx824
Abstract

Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5′ splice site (5′ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5′ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7. We show that Cr1-activating engineered U1 snRNAs (eU1s) have the unique ability to reprogram pre-mRNA splicing and restore exon 7 inclusion in SMN1 carrying a broad spectrum of pathogenic mutations at both the 3′ss and 5′ss of the exon 7. Employing a splicing-coupled translation reporter, we demonstrate that mRNAs generated by an eU1-induced activation of Cr1 produce full-length SMN. Our findings underscore a wider role for U1 snRNP in splicing regulation and reveal a novel approach for the restoration of SMN exon 7 inclusion for a potential therapy of SMA.

Comments

This article is published as Singh, Natalia N., José Bruno Del Rio-Malewski, Diou Luo, Eric W. Ottesen, Matthew D. Howell, and Ravindra N. Singh. "Activation of a cryptic 5′ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene." Nucleic acids research 45, no. 21 (2017): 12214-12240. doi: 10.1093/nar/gkx824. Posted with permission.

Creative Commons License
Creative Commons Attribution 4.0
Copyright Owner
The Authors
Language
en
File Format
application/pdf
Citation Information
Natalia N. Singh, Jose Bruno Del Rio-Malewski, Diou Luo, Eric W. Ottesen, et al.. "Activation of a cryptic 5′ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene" Nucleic Acids Research Vol. 45 Iss. 21 (2017) p. 12214 - 12240
Available at: http://works.bepress.com/ravindra-singh/30/