Facioscapulohumeral muscular dystrophy and DUX4: Breaking the silence

Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands.
Trends in Molecular Medicine (Impact Factor: 9.45). 05/2011; 17(5):252-8. DOI: 10.1016/j.molmed.2011.01.001
Source: PubMed


Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.

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    • "Most FSHD patients harbor a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35, which was 1–10 repeats in FSHD patients and 11–150 repeats in non-affected individuals [22]. The contraction of the D4Z4 repeats resulted in the chromatin remodelling of the 4qter region, activated the expression of the Dux4 gene, a protein that has been regarded as the candidate pathogenic factor of FSHD [4]. The Dux4 gene encoded a protein of 55kd, and can be immunodetected on FSHD myoblast [3] or human testis extracts [23]. "
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    ABSTRACT: It has been implicated that Dux4 plays crucial roles in development of facioscapulohumeral dystrophy. But the underlying myopathic mechanisms and related down-stream events of this retrogene were far from clear. Here, we reported that overexpression of Dux4 in a cell model TE671 reduced cell proliferation rate, and increased G1 phase accumulation. We also determined the impact of Dux4 on p53/p21 signal pathway, which controls the checkpoint in cell cycle progression. Overexpression of Dux4 increased p21 mRNA and protein level, while expression of p53, phospho-p53 remained unchanged. Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. Furthermore, we demonstrated that enhanced Dux4 expression increased p21 promoter activity and elevated expression of Sp1 transcription factor. Mutation of Sp1 binding site decreased dux4 induced p21 promoter activation. Chromatin immunoprecipitation (ChIP) assays confirmed the Dux4-induced binding of Sp1 to p21 promoter in vivo. These results suggest that Dux4 might induce proliferation inhibition and G1 phase arrest through upregulation of p21.
    Biochemical and Biophysical Research Communications 02/2014; 450(1). DOI:10.1016/j.bbrc.2014.02.105 · 2.30 Impact Factor
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    • "FSHD1 (OMIM #158900), the most common type of FSHD, is an autosomal dominant disorder caused by a contraction of the D4Z4 repeat array, a macrosatellite repeat array consisting of 3.3 kb large D4Z4 units located on chromosome 4q. FSHD patients have 1 – 10 repeat units, in contrast to unaffected individuals who have 11 – 100 units [5,6]. Residual repeat length is roughly and inversely correlated to disease severity and onset. "
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    ABSTRACT: Although muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD. Evaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments. This study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.
    BMC Neurology 10/2013; 13(1):144. DOI:10.1186/1471-2377-13-144 · 2.04 Impact Factor
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    • "These arrays are highly polymorphic in copy number, and each of the four alleles usually contains 11 to >150 D4Z4 units, making DUX4 the human proteinencoding gene with the highest overall copy number (Alkan et al. 2009). In FSHD, the chromosome 4 array is contracted to fewer than 11 repeats (Wijmenga et al. 1992; van der Maarel et al. 2011). This is thought to " relax " the D4Z4 chromatin and cause the de-repression and transcription of DUX4 in muscle, where this gene is usually silenced (Snider et al. 2010; Lemmers et al. 2010a). "
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    ABSTRACT: Macrosatellites are large polymorphic tandem arrays. The human subtelomeric macrosatellite D4Z4 has 11-150 repeats, each containing a copy of the intronless DUX4 gene. DUX4 is linked to facioscapulohumeral muscular dystrophy, but its normal function is unknown. The DUX gene family includes DUX4, the intronless Dux macrosatellites in rat and mouse, as well as several intron-containing members (DUXA, DUXB, Duxbl, and DUXC). Here, we report that the genomic organization (though not the syntenic location) of primate DUX4 is conserved in the Afrotheria. In primates and Afrotheria, DUX4 arose by retrotransposition of an ancestral intron-containing DUXC, which is itself not found in these species. Surprisingly, we discovered a similar macrosatellite organization for DUXC in cow and other Laurasiatheria (dog, alpaca, dolphin, pig, and horse), and in Xenarthra (sloth). Therefore, DUX4 and Dux are not the only DUX gene macrosatellites. Our data suggest a new retrotransposition-displacement model for the evolution of intronless DUX macrosatellites.
    Chromosoma 08/2012; 121(5):489-97. DOI:10.1007/s00412-012-0380-y · 4.60 Impact Factor
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