ArticlePLoS genetics2013
Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis.Science advances · 2024Article
- CAPN3: A muscle‑specific calpain with an important role in the pathogenesis of diseases (Review).International journal of molecular medicine · 2021Review
- Exploring the biological role of postzygotic and germinal de novo mutations in ASD.Scientific reports · 2021Article
- RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease.Frontiers in cell and developmental biology · 2021Review
- Diversification of the muscle proteome through alternative splicing.Skeletal muscle · 2018Review
- Review
- Faulty RNA splicing: consequences and therapeutic opportunities in brain and muscle disorders.Human genetics · 2017Review
- Developmental regulation of RNA processing by Rbfox proteins.Wiley interdisciplinary reviews. RNA · 2017Review
- Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation.PloS one · 2016Article
- The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function.Human molecular genetics · 2015Article
- Direct interplay between two candidate genes in FSHD muscular dystrophy.Human molecular genetics · 2015Article
- FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1).PloS one · 2015Article
- Rbfox3 controls the biogenesis of a subset of microRNAs.Nature structural & molecular biology · 2014Article
- Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis.Molecular cell · 2014Article
- A dynamic alternative splicing program regulates gene expression during terminal erythropoiesis.Nucleic acids research · 2014Article
- Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals.Experimental cell research · 2014Review
- Cancer-related genes in the transcription signature of facioscapulohumeral dystrophy myoblasts and myotubes.Journal of cellular and molecular medicine · 2014Article
- Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1).American journal of physiology. Regulatory, integrative and comparative physiology · 2014Article
- RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1.PloS one · 2014Article
- DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy.Skeletal muscle · 2014Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle disease whose molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs, and worms perturbs muscle development and causes FSHD-like phenotypes. FRG1 has been implicated in splicing, and we asked how splicing might be involved in FSHD by conducting a genome-wide analysis in FRG1 mice. We find that splicing perturbations parallel the responses of different muscles to FRG1 over-expression and disease progression. Interestingly, binding sites for the Rbfox family of splicing factors are over-represented in a subset of FRG1-affected splicing events. Rbfox1 knockdown, over-expression, and RNA-IP confirm that these are direct Rbfox1 targets. We find that FRG1 is associated to the Rbfox1 RNA and decreases its stability. Consistent with this, Rbfox1 expression is down-regulated in mice and cells over-expressing FRG1 as well as in FSHD patients. Among the genes affected is Calpain 3, which is mutated in limb girdle muscular dystrophy, a disease phenotypically similar to FSHD. In FRG1 mice and FSHD patients, the Calpain 3 isoform lacking exon 6 (Capn3 E6-) is increased. Finally, Rbfox1 knockdown and over-expression of Capn3 E6- inhibit muscle differentiation. Collectively, our results suggest that a component of FSHD pathogenesis may arise by over-expression of FRG1, reducing Rbfox1 levels and leading to aberrant expression of an altered Calpain 3 protein through dysregulated splicing.
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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.