ArticlePloS one2013
Multiple protein domains contribute to nuclear import and cell toxicity of DUX4, a candidate pathogenic protein for facioscapulohumeral muscular dystrophy.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome.Communications biology · 2024Pooled it
- DUX4 at 25: how it emerged from "junk DNA" to become the cause of facioscapulohumeral muscular dystrophy.Skeletal muscle · 2025Review
- The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.International journal of molecular sciences · 2025Review
- MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.Cell reports · 2023Article
- Post-Translational Modifications of the DUX4 Protein Impact Toxic Function in FSHD Cell Models.Annals of neurology · 2023Article
- WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy.Nucleic acids research · 2023Article
- Influence ofInternational journal of molecular sciences · 2023Review
- Downstream events initiated by expression of FSHD-associated DUX4: Studies of nucleocytoplasmic transport, γH2AX accumulation, and Bax/Bak-dependence.Biology open · 2022Article
- Review
- Induction of a local muscular dystrophy using electroporation in vivo: an easy tool for screening therapeutics.Scientific reports · 2020Article
- Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity.Skeletal muscle · 2020Article
- DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle.Human molecular genetics · 2018Review
- Functional domains of the FSHD-associated DUX4 protein.Biology open · 2018Article
- Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity.The Journal of clinical investigation · 2017Article
- Article
- PARP1 Differentially Interacts with Promoter region ofJournal of genetic syndromes & gene therapy · 2016Article
- Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.Nature genetics · 2016Article
- Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation.PloS one · 2016Article
- Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.Skeletal muscle · 2014Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DUX4 (Double Homeobox Protein 4) is a nuclear transcription factor encoded at each D4Z4 unit of a tandem-repeat array at human chromosome 4q35. DUX4 constitutes a major candidate pathogenic protein for facioscapulohumeral muscular dystrophy (FSHD), the third most common form of inherited myopathy. A low-level expression of DUX4 compromises cell differentiation in myoblasts and its overexpression induces apoptosis in cultured cells and living organisms. In this work we explore potential molecular determinants of DUX4 mediating nuclear import and cell toxicity. Deletion of the hypothetical monopartite nuclear localization sequences RRRR(23), RRKR(98) and RRAR(148) (i.e. NLS1, NLS2 and NLS3, respectively) only partially delocalizes DUX4 from the cell nuclei. Nuclear entrance guided by NLS1, NLS2 and NLS3 does not follow the classical nuclear import pathway mediated by α/β importins. NLS and homeodomain mutants from DUX4 are dramatically less cell-toxic than the wild type molecule, independently of their subcellular localization. A triple ΔNLS1-2-3 deletion mutant is still partially localized in the nuclei, indicating that additional sequences in DUX4 contribute to nuclear import. Deletion of ≥111 amino acids from the C-terminal of DUX4, on a ΔNLS1-2-3 background, almost completely re-localizes DUX4 to the cytoplasm, indicating that the C-ter tail contributes to subcellular trafficking of DUX4. Also, C-terminal deletion mutants of DUX4 on a NLS wild type background are less toxic than wild type DUX4. Results reported here indicate that DUX4 possesses redundant mechanisms to assure nuclear entrance and that its various transcription-factor associated domains play an essential role in cell toxicity.
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