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.
    Chromosoma 08/2012; 121(5):489-97. DOI:10.1007/s00412-012-0380-y · 3.26 Impact Factor
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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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    ABSTRACT: We performed a detailed genomic investigation of the chimpanzee locus syntenic to human chromosome 4q35.2, associated to the facioscapulohumeral dystrophy. Two contigs of approximately 150kb and 200kb were derived from PTR chromosomes 4q35 and 3p12, respectively: both regions showed a very similar sequence organization, including D4Z4 and Beta satellite linked clusters. Starting from these findings, we derived a hypothetical evolutionary history of human 4q35, 10q26 and 3p12 chromosome regions focusing on the D4Z4-Beta satellite linked organization. The D4Z4 unit showed an open reading frame (DUX4) at both PTR 4q35 and 3p12 regions; furthermore some subregions of the Beta satellite unit showed a high degree of conservation between chimpanzee and humans. In conclusion, this paper provides evidence that at the 4q subtelomere the linkage between D4Z4 and Beta satellite arrays is a feature that appeared late during evolution and is conserved between chimpanzee and humans.
    Genomics 07/2012; 100(5). DOI:10.1016/j.ygeno.2012.07.011 · 2.79 Impact Factor
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    • "Although some of our variants might occur due to systemic errors in NGS compared to the Sanger method used to generate the human genome reference sequence (Balasubramanian, et al., 2011; van der Maarel, et al., 2011), comparing NGS of exomes with that of Illumina genomes confirmed that the vast majority of the variant genotypes were correctly called. For 85% (863/1009) of the ES homozygous non-RefSeq genotypes, we also found concordance in more than 50 of the 69 publically available Complete Genomics genomes. "
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    ABSTRACT: Disease gene discovery has been transformed by affordable sequencing of exomes and genomes. Identification of disease-causing mutations requires sifting through a large number of sequence variants. A subset of the variants are unlikely to be good candidates for disease causation based on one or more of the following criteria: (1) being located in genomic regions known to be highly polymorphic, (2) having characteristics suggesting assembly misalignment, and/or (3) being labeled as variants based on misleading reference genome information. We analyzed exome sequence data from 118 individuals in 29 families seen in the NIH Undiagnosed Diseases Program (UDP) to create lists of variants and genes with these characteristics. Specifically, we identified several groups of genes that are candidates for provisional exclusion during exome analysis: 23,389 positions with excess heterozygosity suggestive of alignment errors and 1,009 positions in which the hg18 human genome reference sequence appeared to contain a minor allele. Exclusion of such variants, which we provide in supplemental lists, will likely enhance identification of disease-causing mutations using exome sequence data.
    Human Mutation 04/2012; 33(4):609-13. DOI:10.1002/humu.22033 · 5.05 Impact Factor
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