ArticleHuman molecular genetics2010
A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 83 citations in OpenAlex.
- An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.bioRxiv : the preprint server for biology · 2024Article
- 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
- Sleep and sleep-related breathing disorders in patients with spinal muscular atrophy: a changing perspective from novel treatments?Frontiers in neurology · 2024Review
- Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.Frontiers in RNA research · 2024Article
- U1 snRNA interactions with deep intronic sequences regulate splicing of multiple exons of spinal muscular atrophy genes.Frontiers in neuroscience · 2024Article
- Cerebellar structural, astrocytic, and neuronal abnormalities in the SMNΔ7 mouse model of spinal muscular atrophy.Brain pathology (Zurich, Switzerland) · 2023Article
- Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment.International journal of molecular sciences · 2023Review
- A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses.Neuron · 2023Article
- The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration.International journal of molecular sciences · 2023Review
- Spinal muscular atrophy.Nature reviews. Disease primers · 2022Review
- Article
- The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.Biomedicines · 2021Review
- Targeting the 5' untranslated region ofMolecular therapy. Nucleic acids · 2021Article
- Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy.Life science alliance · 2021Article
- The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases.Molecular systems biology · 2020Article
- Circulating microRNAs as potential biomarkers and therapeutic targets in spinal muscular atrophy.Therapeutic advances in neurological disorders · 2020Review
- Review
- Auto-regulatory feedback by RNA-binding proteins.Journal of molecular cell biology · 2019Review
- Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.Genes & development · 2018Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is a neurological disorder characterized by motor neuron degeneration and progressive muscle paralysis. The disease is caused by a reduction in survival of motor neuron (SMN) protein resulting from homozygous deletion of the SMN1 gene. SMN protein is also encoded by SMN2. However, splicing of SMN2 exon 7 is defective, and consequently, the majority of the transcripts produce a truncated, unstable protein. SMN protein itself has a role in splicing. The protein is required for the biogenesis of spliceosomal snRNPs, which are essential components of the splicing reaction. We now show that SMN protein abundance affects the splicing of SMN2 exon 7, revealing a feedback loop inSMN expression. The reduced SMN protein concentration observed in SMA samples and in cells depleted of SMN correlates with a decrease in cellular snRNA levels and a decrease in SMN2 exon 7 splicing. Furthermore, altering the relative abundance or activity of individual snRNPs has distinct effects on exon 7 splicing, demonstrating that core spliceosomal snRNPs influence SMN2 alternative splicing. Our results identify a feedback loop in SMN expression by which low SMN protein levels exacerbate SMN exon 7 skipping, leading to a further reduction in SMN protein. These results imply that a modest increase in SMN protein abundance may cause a disproportionately large increase in SMN expression, a finding that is important for assessing the therapeutic potential of SMA treatments and understanding disease pathogenesis.
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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 OpenQuestion graph.