ArticleHuman molecular genetics2012
Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS).Nature communications · 2024Article
- Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts.Protein science : a publication of the Protein Society · 2023Article
- Heat increases full-length SMN splicing: promise for splice-augmenting therapies for SMA.Human genetics · 2022Article
- Revisiting the role of mitochondria in spinal muscular atrophy.Cellular and molecular life sciences : CMLS · 2021Review
- Spinal muscular atrophy: Broad disease spectrum and sex-specific phenotypes.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige.Cellular and molecular life sciences : CMLS · 2021Review
- Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA.Annals of clinical and translational neurology · 2020Article
- Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer.Journal of experimental & clinical cancer research : CR · 2020Review
- Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates.Current genomics · 2018Review
- Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.Genes & development · 2018Article
- Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells.BMC cancer · 2018Article
- Systematic Analysis of Gene Expression Profiles Controlled by hnRNP Q and hnRNP R, Two Closely Related Human RNA Binding Proteins Implicated in mRNA Processing Mechanisms.Frontiers in molecular biosciences · 2018Article
- SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities.Human genetics · 2017Review
- Emerging therapies and challenges in spinal muscular atrophy.Annals of neurology · 2017Review
- Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art.Neuropathology and applied neurobiology · 2015Review
- Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy.Future medicinal chemistry · 2015Review
- Pathological impact of SMN2 mis-splicing in adult SMA mice.EMBO molecular medicine · 2013Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease associated with low levels of the essential survival motor neuron (SMN) protein. Reduced levels of SMN is due to the loss of the SMN1 gene and inefficient splicing of the SMN2 gene caused by a C>T mutation in exon 7. Global analysis of the severe SMNΔ7 SMA mouse model revealed altered splicing and increased levels of the hypoxia-inducible transcript, Hif3alpha, at late stages of disease progression. Severe SMA patients also develop respiratory deficiency during disease progression. We sought to evaluate whether hypoxia was capable of altering SMN2 exon 7 splicing and whether increased oxygenation could modulate disease in a severe SMA mouse model. Hypoxia treatment in cell culture increased SMN2 exon 7 skipping and reduced SMN protein levels. Concordantly, the treatment of SMNΔ7 mice with hyperoxia treatment increased the inclusion of SMN2 exon 7 in skeletal muscles and resulted in improved motor function. Transfection splicing assays of SMN minigenes under hypoxia revealed that hypoxia-induced skipping is dependent on poor exon definition due to the SMN2 C>T mutation and suboptimal 5' splice site. Hypoxia treatment in cell culture led to increased hnRNP A1 and Sam68 levels. Mutation of hnRNP A1-binding sites prevented hypoxia-induced skipping of SMN exon 7 and was found to bind both hnRNP A1 and Sam68. These results implicate hypoxic stress as a modulator of SMN2 exon 7 splicing in disease progression and a coordinated regulation by hnRNP A1 and Sam68 as modifiers of hypoxia-induced skipping of SMN exon 7.
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Registered trials
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