Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.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.
Ansseau,
DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation.
2009, Pubmed
Ansseau,
DUX4c is up-regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation.
2009,
Pubmed
Barro,
Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects.
2010,
Pubmed
Bodega,
Remodeling of the chromatin structure of the facioscapulohumeral muscular dystrophy (FSHD) locus and upregulation of FSHD-related gene 1 (FRG1) expression during human myogenic differentiation.
2009,
Pubmed
Bopp,
Conservation of a large protein domain in the segmentation gene paired and in functionally related genes of Drosophila.
1986,
Pubmed
Bosnakovski,
Biphasic myopathic phenotype of mouse DUX, an ORF within conserved FSHD-related repeats.
2009,
Pubmed
,
Xenbase
Bosnakovski,
DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation.
2008,
Pubmed
Bosnakovski,
An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.
2008,
Pubmed
Buckingham,
Myogenic progenitor cells and skeletal myogenesis in vertebrates.
2006,
Pubmed
Chang,
xPitx1 plays a role in specifying cement gland and head during early Xenopus development.
2001,
Pubmed
,
Xenbase
Clapp,
Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.
2007,
Pubmed
Cole,
Expression of limb initiation genes and clues to the morphological diversification of threespine stickleback.
2003,
Pubmed
Dixit,
DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.
2007,
Pubmed
Finkelstein,
The orthodenticle gene encodes a novel homeo domain protein involved in the development of the Drosophila nervous system and ocellar visual structures.
1990,
Pubmed
Fitzsimons,
Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy. A general association with genetic and therapeutic implications.
1987,
Pubmed
Gabellini,
Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1.
2006,
Pubmed
Gabellini,
Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.
2002,
Pubmed
Gabriëls,
Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.
1999,
Pubmed
Hanel,
Muscular dystrophy candidate gene FRG1 is critical for muscle development.
2009,
Pubmed
,
Xenbase
Harland,
In situ hybridization: an improved whole-mount method for Xenopus embryos.
1991,
Pubmed
,
Xenbase
Hensey,
A developmental timer that regulates apoptosis at the onset of gastrulation.
1997,
Pubmed
,
Xenbase
Hewitt,
Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.
1994,
Pubmed
Hollemann,
Xpitx-1: a homeobox gene expressed during pituitary and cement gland formation of Xenopus embryos.
1999,
Pubmed
,
Xenbase
Jiang,
Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.
2003,
Pubmed
Kawazu,
Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development.
2007,
Pubmed
Klooster,
Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level.
2009,
Pubmed
Kowaljow,
The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.
2007,
Pubmed
Lanctôt,
Hindlimb patterning and mandible development require the Ptx1 gene.
1999,
Pubmed
Liu,
Transcriptional activation of p53 by Pitx1.
2007,
Pubmed
Logan,
Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity.
1999,
Pubmed
Morosetti,
Isolation and characterization of mesoangioblasts from facioscapulohumeral muscular dystrophy muscle biopsies.
2007,
Pubmed
Olguin,
Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal.
2004,
Pubmed
Padberg,
On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy.
1995,
Pubmed
Padberg,
On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy.
1995,
Pubmed
Reed,
Abnormal expression of mu-crystallin in facioscapulohumeral muscular dystrophy.
2007,
Pubmed
Relaix,
Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells.
2006,
Pubmed
Rijkers,
FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients.
2004,
Pubmed
Sandri,
Caspase 3 expression correlates with skeletal muscle apoptosis in Duchenne and facioscapulo human muscular dystrophy. A potential target for pharmacological treatment?
2001,
Pubmed
Schweickert,
Pitx1 and Pitx2c are required for ectopic cement gland formation in Xenopus laevis.
2001,
Pubmed
,
Xenbase
Shapiro,
Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks.
2004,
Pubmed
Simeone,
The Otx family.
2002,
Pubmed
Snider,
RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.
2009,
Pubmed
Szeto,
Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development.
1999,
Pubmed
Tajbakhsh,
Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD.
1997,
Pubmed
Tanaka,
Developmental genetic basis for the evolution of pelvic fin loss in the pufferfish Takifugu rubripes.
2005,
Pubmed
Tremblay,
Transcriptional properties of Ptx1 and Ptx2 isoforms.
2000,
Pubmed
van Deutekom,
FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit.
1993,
Pubmed
van Overveld,
Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.
2003,
Pubmed
Wijmenga,
Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.
1992,
Pubmed
Winokur,
Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation.
2003,
Pubmed
Winokur,
The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region.
1996,
Pubmed
Winokur,
Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress.
2003,
Pubmed
Wright,
Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11.
1993,
Pubmed
Wu,
Characterization of genomic structures and expression profiles of three tandem repeats of a mouse double homeobox gene: Duxbl.
2010,
Pubmed
Wuebbles,
FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy.
2009,
Pubmed
,
Xenbase
