ArticleNucleic acids research2017
Activation of a cryptic 5' splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene.
Article in Nucleic acids research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 30 citations in OpenAlex.
- Nusinersen: the antisense oligonucleotide at the forefront of spinal muscular atrophy treatment.RNA biology · 2026Review
- Utargetome: A targetome prediction tool for modified U1-snRNAs to identify distal-target positions with improved selectivity.PLoS computational biology · 2025Article
- Pre-mRNA Splicing Modulation by Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2025Article
- A super minigene with a short promoter and truncated introns recapitulates essential features of transcription and splicing regulation of the SMN1 and SMN2 genes.Nucleic acids research · 2024Article
- Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.Acta neuropathologica · 2024Article
- U1 snRNA interactions with deep intronic sequences regulate splicing of multiple exons of spinal muscular atrophy genes.Frontiers in neuroscience · 2024Article
- Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy.Nucleic acids research · 2023Article
- Revealing diverse alternative splicing variants of the highly homologous SMN1 and SMN2 genes by targeted long-read sequencing.Molecular genetics and genomics : MGG · 2022Article
- Internal Introns Promote Backsplicing to Generate Circular RNAs from Spinal Muscular Atrophy Gene.Genes · 2022Article
- Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene.Frontiers in molecular biosciences · 2022Review
- A high-throughput genome-wide RNAi screen identifies modifiers of survival motor neuron protein.Cell reports · 2021Article
- Profiling of cis- and trans-acting factors supporting noncanonical splice site activation.RNA biology · 2021Article
- Characteristics of circular RNAs generated by human Survival Motor Neuron genes.Cellular signalling · 2020Review
- A survey of transcripts generated by spinal muscular atrophy genes.Biochimica et biophysica acta. Gene regulatory mechanisms · 2020Review
- RNA in spinal muscular atrophy: therapeutic implications of targeting.Expert opinion on therapeutic targets · 2020Review
- The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy.Neuroscience insights · 2020Review
- Therapeutic approaches to treat human spliceosomal diseases.Current opinion in biotechnology · 2019Review
- High-throughput analysis revealed mutations' diverging effects onRNA biology · 2019Article
- Rescue of spinal muscular atrophy mouse models with AAV9-Exon-specific U1 snRNA.Nucleic acids research · 2019Article
- Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.PLoS genetics · 2019Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.