Muscular dystrophy candidate gene FRG1 is critical for muscle development

Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Developmental Dynamics (Impact Factor: 2.38). 06/2009; 238(6):1502-12. DOI: 10.1002/dvdy.21830
Source: PubMed


The leading candidate gene responsible for facioscapulohumeral muscular dystrophy (FSHD) is FRG1 (FSHD region gene 1). However, the correlation of altered FRG1 expression levels with disease pathology has remained controversial and the precise function of FRG1 is unknown. Here, we carried out a detailed analysis of the normal expression patterns and effects of FRG1 misexpression during vertebrate embryonic development using Xenopus laevis. We show that frg1 is expressed in and essential for the development of the tadpole musculature. FRG1 morpholino injection disrupted myotome organization and led to inhibited myotome growth, while elevated FRG1 led to abnormal epaxial and hypaxial muscle formation. Thus, maintenance of normal FRG1 levels is critical for proper muscle development, supportive of FSHD disease models whereby misregulation of FRG1 plays a causal role underlying the pathology exhibited in FSHD patients. Developmental Dynamics 238:1502-1512, 2009. (c) 2008 Wiley-Liss, Inc.

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Available from: Peter L Jones, Aug 15, 2014
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    • "On the other hand, seventeen genes exist on deleted segment of 2.449 Mb at 4q35.2. Among the genes that were shown in Table 1, only FRG1 and FRG2 genes were considered to relate with facioscapulohumeral muscular dystrophy [15]. Hemizygosity of deleted 23 genes on 4p and 4q of ring chromosome have risk of clinical pathologies at the postnatal period. "
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    ABSTRACT: Ring chromosomes are unusual abnormalities that are observed in prenatal diagnosis. A 23-year-old patient (gravida 1, para 0) referred for amniocentesis due to abnormal maternal serum screening result in the 16th week of second pregnancy. Cytogenetic analysis of cultured amniyotic fluid cells revealed out ring chromosome 4. Both maternal and paternal karyotypes were normal. Terminal deletion was observed in both 4p and 4q arms of ring chromosome 4 by fluorescence in situ hybridization (FISH). However deletion was not observed in the WHS critical region of both normal and ring chromosome 4 by an additional FISH study. These results were confirmed by means of array-CGH showing terminal deletions on 4p16.3 (130 kb) and 4q35.2 (2.449 Mb). In the 21th week of pregnancy, no gross anomalia, except two weeks symmetric growth retardation, was present in the fetal ultrasonographic examination. According to our review of literature, this is the first prenatal case with 4p and 4q subtelomeric deletion of ring chromosome 4 without the involvement of WHS critical region. Our report describes the prenatal case with a ring chromosome 4 abnormality completely characterized by array-CGH which provided complementary data for genetic counseling of prenatal diagnosis.
    12/2013; 2013:248050. DOI:10.1155/2013/248050
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    • "A growing understanding of its function, strongly suggests that FRG1 overexpression plays an important role in FSHD.16,17,18,45 Based on these data, FRG1 inhibition would be expected to lead to a therapeutic benefit in FSHD. "
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    ABSTRACT: Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.
    Molecular Therapy 08/2011; 19(11):2055-64. DOI:10.1038/mt.2011.153 · 6.23 Impact Factor
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    • "Facioscapulohumeral muscular dystrophy region gene-1 (FRG1) is an actin-bundling protein associated with muscle-attachment sites, specifically located to the Z-disc in mature muscle tissue [34], [35]. FRG1 has been shown to play a crucial and specific role in muscle development of Xenopus laevis, further implicating its importance in muscle development and maintenance [36], [37]. Recently, Bodega et al. showed that the FRG1 gene was prematurely expressed during FSHD myoblast differentiation, thereby suggesting that the number of D4Z4 repeats in the array may affect the correct timing of FRG1 expression [27]. "
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    ABSTRACT: Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD.
    PLoS ONE 05/2011; 6(5):e19780. DOI:10.1371/journal.pone.0019780 · 3.23 Impact Factor
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