Journal
NUCLEIC ACIDS RESEARCH
Volume 45, Issue 21, Pages 12214-12240Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx824
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Funding
- National Institutes of Health [R01 NS055925, R21 NS101312]
- Iowa Center for Advanced Neurotoxicology (ICAN)
- NIH [R01 NS055925, R21 NS101312]
- Salsbury Endowment (Iowa State University, Ames, IA, USA)
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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 fromSMN1 that carries a pathogenic G-to-Cmutation 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 splicingcoupled 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.
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