Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.
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| http://dx.doi.org/10.1016/j.devcel.2011.11.013 | DOI Listing |
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Unlabelled: RNA-driven protein aggregation leads to cellular dysregulation by sequestering regulatory proteins, disrupting normal cellular processes, and contributing to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar-associated RNA and human satellite II (HSATII) repeat RNA. Stable intranuclear RNAs drive protein aggregation in DUX4-expressing muscle cells.
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Aix-Marseille Univ-INSERM, Marseille Medical Genetics, Marseille, France.
The molecular diagnosis of type 1 facioscapulohumeral muscular dystrophy (FSHD1) relies on the detection of a shortened D4Z4 array at the 4q35 locus. Until recently, the diagnosis of FSHD2 relied solely on the absence of a shortened D4Z4 allele in clinically affected patients. It is now established that most FSHD2 cases carry a heterozygous variant in the SMCHD1 gene.
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From the Department of Neurology (J.N.D., H.T.M.B., N.V.A., B.G.M.V.E., N.C.V.); Department of Pediatric Neurology (J.N.D., H.T.M.B., A.K., C.E.E.), Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Neurology (R.J.M.G.), Jönköping, and Department of Biomedical and Clinical Sciences, Linköping University, Sweden; Department of Rehabilitation (M.M.P., S.L.S.H.), Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital; and Department of Neurology (N.V.A.), Clinical Neuromuscular Imaging Group, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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Department of Genetics, Harvard Medical School, Boston, MA.
Article Synopsis
- - The study focuses on Facioscapulohumeral dystrophy type 1 (FSHD1), a serious muscle disorder, and emphasizes the need for a comprehensive approach to understand its genetics.
- - Researchers conducted genome sequencing and linkage analysis in a family suspected of having FSHD1, identifying a specific disease locus on chromosome 4q35.2.
- - By using advanced ultra-long-read genome sequencing, they successfully genotyped a pathogenic allele associated with FSHD1, highlighting the effectiveness of these genomic tools in disease mapping and characterization.
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