Activation of a cryptic 5′ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene

dc.contributor.author Ottesen, Eric
dc.contributor.author Singh, Natalia
dc.contributor.author Del Rio-Malewski, Jose Bruno
dc.contributor.author Luo, Diou
dc.contributor.author Singh, Ravindra
dc.contributor.author Ottesen, Eric
dc.contributor.author Howell, Matthew
dc.contributor.author Singh, Ravindra
dc.contributor.department Biomedical Sciences
dc.contributor.department Genetics and Genomics
dc.date 2018-02-22T06:04:15.000
dc.date.accessioned 2020-06-30T00:53:28Z
dc.date.available 2020-06-30T00:53:28Z
dc.date.copyright Sun Jan 01 00:00:00 UTC 2017
dc.date.issued 2017-12-01
dc.description.abstract <p>Spinal muscular atrophy (SMA) is caused by deletions or mutations of the <em>Survival Motor Neuron 1</em> (<em>SMN1</em>) gene coupled with predominant skipping of <em>SMN2</em> 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 <em>SMN1</em> 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 <em>SMN1</em> 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 <em>SMN</em> exon 7 inclusion for a potential therapy of SMA.</p>
dc.description.comments <p>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." <em>Nucleic acids research</em> 45, no. 21 (2017): 12214-12240. doi: <a href="https://doi.org/10.1093/nar/gkx824">10.1093/nar/gkx824</a>. Posted with permission.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/bms_pubs/55/
dc.identifier.articleid 1053
dc.identifier.contextkey 11607131
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath bms_pubs/55
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/11181
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/bms_pubs/55/2017_RSingh_ActivationCryptic.pdf|||Sat Jan 15 00:55:24 UTC 2022
dc.source.uri 10.1093/nar/gkx824
dc.subject.disciplines Cell and Developmental Biology
dc.subject.disciplines Comparative and Laboratory Animal Medicine
dc.subject.disciplines Genetics and Genomics
dc.subject.disciplines Molecular Genetics
dc.title Activation of a cryptic 5′ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication 30dd0ac9-28a2-4363-bac0-4f19aa596e2f
relation.isAuthorOfPublication d5765265-0e5d-4de9-8e17-19842ab75544
relation.isOrgUnitOfPublication 184db3f2-d93f-4571-8ad7-07c8a9e6a5c9
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