Article

Biphasic myopathic phenotype of mouse DUX, an ORF conserved FSHD-related repeats

Brunel University, United Kingdom
PLoS ONE (Impact Factor: 3.23). 09/2009; 4(9):e7003. DOI: 10.1371/journal.pone.0007003
Source: PubMed

ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is caused by contractions of D4Z4 repeats at 4q35.2 thought to induce misregulation of nearby genes, one of which, DUX4, is actually localized within each repeat. A conserved ORF (mDUX), embedded within D4Z4-like repeats, encoding a double-homeodomain protein, was recently identified on mouse chromosome 10. We show here that high level mDUX expression induces myoblast death, while low non-toxic levels block myogenic differentiation by down-regulating MyoD and Myf5. Toxicity and MyoD/Myf5 expression changes were competitively reversed by overexpression of Pax3 or Pax7, implying mechanistic similarities with the anti-myogenic activity of human DUX4. We tested the effect of mDUX expression on Xenopus development, and found that global overexpression led to abnormalities in gastrulation. When targeted unilaterally into blastomeres fated to become tail muscle in 16-cell embryos, mDUX caused markedly reduced tail myogenesis on the injected side. These novel cell and animal models highlight the myopathic nature of sequences within the FSHD-related repeat array.

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    • "Searching for Putative Duxbl Ortholog Although the genomic structure of Duxbl is more similar to human DUXA gene than human DUX4 gene, the predicted amino acid sequences of homeodomains for Duxbl and DUX4 proteins are more similar (H1: 42% identity; H2: 67% identity) than those of Duxbl and DUXA proteins (H1: 35% identity; H2: 53% identity; Fig. 1C). Recently, a mouse representative of D4Z4 on chromosome 10 was identified and named as Dux (Clapp et al., 2007) and mDUX (Bosnakovski et al., 2009), respectively. However, sequence identities of the predicted protein and DUX4 homeodomains (H1: 36% identity; H2: 56% identity ) are also lower than those of Duxbl and DUX4. "
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    ABSTRACT: We identified and cloned a mouse double homeobox gene (Duxbl), which encodes two homeodomains. Duxbl gene, a tandem triplicate produces two major transcripts, Duxbl and Duxbl-s. The amino acid sequences of Duxbl homeodomains are most similar to those of human DUX4 protein, associated with facioscapulohumeral muscular dystrophy. In adult tissues, Duxbl is predominantly expressed in female reproductive organs and eyes, and slightly expressed in brain and testes. During gonad development, Duxbl is expressed from embryonic to adult stages and specifically expressed in oocytes and spermatogonia. During embryonic development, Duxbl is transcribed in limbs and tail. However, Duxbl proteins were only detected in trunk and limb muscles and in elongated myocytes and myotubes. In C2C12 muscle cell line, Duxbl expression pattern is similar to differentiated marker gene, Myogenin, increased in expression from 2 days onward in differentiating medium. We suggest that Duxbl proteins play regulatory roles during myogenesis and reproductive developments.
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    • "In fact, when considering the entire protein sequence, including that residing outside their homeodomains, they both completely lack evolutionary conservation and appear to be unique to humans. Even the most closely related DUX4 ORFs in mice [31] [32] [33] [34] show levels of sequence similarity (31% amino acid identity for the Duxbl protein aligned to DUX4 using the ClustalW function of BioEdit Sequence Alignment Editor software) far below what is expected for mouse to human conservation. Without any clear ortholog available, the human sequences for DUX4 and DUX4c were used for these studies. "
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    ABSTRACT: The genetic lesion leading to facioscapulohumeral muscular dystrophy (FSHD) is a dominant deletion at the 4q35 locus. The generally accepted disease model involves an epigenetic dysregulation in the region resulting in the upregulation of one or more proximal genes whose overexpression specifically affects skeletal muscle. However, multiple FSHD candidate genes have been proposed without clear consensus. Using Xenopus laevis as a model for vertebrate development our lab has studied the effects of overexpression of the FSHD candidate gene ortholog, frg1 (FSHD region gene 1), showing that increased levels of frg1 systemically led specifically to an abnormal musculature and increased angiogenesis, the two most prominent clinical features of FSHD. Here we studied the overexpression effects of three other promising FSHD candidate genes, DUX4, DUX4c, and PITX1 using the same model system and methods for direct comparison. Expression of even very low levels of either DUX4 or pitx1 early in development led to massive cellular loss and severely abnormal development. These abnormalities were not muscle specific. In contrast, elevated levels of DUX4c resulted in no detectable adverse affects on muscle and DUX4c levels did not alter the expression of myogenic regulators. This data supports a model for DUX4 and PITX1 in FSHD only as pro-apoptotic factors if their expression in FSHD is confined to cells within the myogenic pathway; neither could account for the vascular pathology prevalent in FSHD. Taken together, increased frg1 expression alone leads to a phenotype that most closely resembles the pathophysiology observed in FSHD patients.
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