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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: 10.11). 05/2011; 17(5):252-8. DOI: 10.1016/j.molmed.2011.01.001
Source: PubMed

ABSTRACT 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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    • "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.
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    • "The importance of this repetitive sequence organization for human cell physiology can be derived from the observation that D4Z4 array contraction of the 4qA allele causes a type of muscle dystrophy (FSHD) [8] [9] [10]. There is a general consensus in the field that D4Z4 deletion leads to epigenetic alterations that affect the expression profiles of in cis candidate genes (for review see [9] [10] [34]). Potential FSHD candidate genes are ANT1 (SLC25A4), FRG1, FRG2, DUX4 and DUX4c and in this regard in the last years many papers have attempted to define the " true " candidate gene(s) without conclusive results. "
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