Muscular dystrophy candidate gene FRG1 is critical for muscle development

Hanel, Meredith L.; Wuebbles, Ryan D.; Jones, Peter L.

doi:10.1002/dvdy.21830

Cited by 46 publications

(56 citation statements)

References 21 publications

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“…Interestingly frg1 overexpression in this invertebrate model disrupts the body-wall musculature and the muscular organization (Liu et al, 2010). In Xenopus both knock down and overexpression of frg1 resulted in defective growth and morphogenesis of the myotome indicating that precise levels of frg1 must be maintained for normal muscle morphology (Hanel et al, 2009). Together these results strongly suggest an evolutionary conserved function of FRG1 in muscular development.…”

Section: Fshd Region Gene 1 (Frg1)mentioning

confidence: 71%

See 1 more Smart Citation

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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Section: Fshd Region Gene 1 (Frg1)mentioning

confidence: 71%

“…Recent studies show the crucial role of FRG1 in maintaining proper muscle structure and function (Hanel et al, 2011;Hanel et al, 2009;Liu et al, 2010). In C. elegans, frg1 protein localized both in nuclei and in the dense bodies that are homologous to vertebrate Z-disk.…”

Section: Fshd Region Gene 1 (Frg1)mentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Salani¹,

Morini²,

Scionti³

et al. 2012

Neuromuscular Disorders

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“…Scale bars: 50m. orthologs in Xenopus, M. musculus and now C. elegans (Gabellini et al, 2006;Hanel et al, 2009), and the conserved actin-bundling activity of the human FRG1 protein, we propose that FRG1 is likely to localize and function similarly in human muscle (Fig. 4M).…”

Section: Translational Impact Relating To Fshd Pathophysiologymentioning

confidence: 81%

“…However, multiple expression analyses have produced inconclusive, and often contradictory, results with respect to altered mRNA expression levels in FSHD-affected muscle (Arashiro et al, 2009;Gabellini et al, 2006;Jiang et al, 2003;Osborne et al, 2007;Winokur et al, 2003). Circumventing the inconsistencies of the RNA expression data, both mice and Xenopus transgenically overexpressing FRG1 in skeletal muscle exhibit FSHD-like phenotypes (Gabellini et al, 2006;Hanel et al, 2009;). In addition, ubiquitous FRG1 overexpression not only disrupts normal vertebrate muscle development, but also leads to a tortuous vasculature similar to the retinal vasculopathy exhibited by more than 50% of FSHD patients (Gieron et al, 1985;Wuebbles et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Facioscapulohumeral muscular dystrophy region gene-1 (FRG-1) is an actin-bundling protein associated with muscle-attachment sites

Liu

Jones

Tang

et al. 2010

Journal of Cell Science

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SummaryIn vertebrates, overexpression of facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) recapitulates the pathophysiology exhibited by FSHD patients, although the role of FRG1 in FSHD remains controversial and no precise function for FRG1 has been described in any organism. To gain insight into the function and potential role of FRG1 in FSHD, we analyzed the highly conserved Caenorhabditis elegans ortholog, frg-1. C. elegans body-wall muscles contain two distinct subcellular pools of FRG-1: nuclear FRG-1, concentrated in the nucleoli; and cytoplasmic FRG-1, associated with the Z-disk and costamere-like structures known as dense bodies. Functionally, we demonstrate that FRG-1 is an F-actin-bundling protein, consistent with its localization to dense bodies; this activity is conserved in human FRG1. This is particularly intriguing because it places FRG-1 along side the list of densebody components whose vertebrate orthologs are involved in the myriad myopathies associated with disrupted costameres and Z-disks. Interestingly, overexpressed FRG-1 preferentially accumulates in the nucleus and, when overexpressed specifically from the frg-1 promoter, disrupts the adult ventral muscle structure and organization. Together, these data further support a role for FRG1 overexpression in FSHD pathophysiology and reveal the previously unsuspected direct involvement of FRG-1 in muscle structure and integrity. Key words: FSHD, Dense body, Muscle, FRG1, Muscular dystrophy, ActinJournal of Cell Science 1117 FRG-1 is a dense-body actin bundler analyzed the C. elegans ortholog of FRG1, frg-1 (ZK1010.3), with respect to biological activity, expression and subcellular distribution in body-wall muscle and the effects of FRG-1 overexpression on the adult body-wall musculature. Results FRG-1 is a conserved actin-bundling proteinFRG1 is highly evolutionarily conserved among vertebrates and invertebrates (Grewal et al., 1998), with human FRG1 sharing 42% identity (58% similarity) with C. elegans FRG-1 over the full length of the protein (Fig. 1); however, its function has remained elusive. Analysis of the predicted amino acid sequence for the presence of conserved domains (Pfam 23.0, http://pfam.sanger.ac.uk/) revealed that FRG-1, as with all other FRG1 orthologs, contains a single fascin-like domain (PF06220), indicative of an actin-binding protein (Adams, 2004;Edwards and Bryan, 1995). To determine whether FRG-1 could, in fact, bind F-actin, high-speed actin cosedimentation assays were performed ( Fig. 2A). Recombinant FRG-1 (supplementary material Fig. S1A) was incubated with Factin for 2 hours and then centrifuged at 100,000ϫg to pellet all F-actin and F-actin-bound FRG-1. The amount of FRG-1 in the pellets (F-actin-FRG-1) and supernatants (free FRG-1) was determined by gel electrophoresis. Saturable F-actin binding was reproducibly achieved by the co-sedimentation of increasing concentrations of recombinant FRG-1 with a fixed amount of Factin. Nonlinear regression analysis of the binding data from four independent ...

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“…Consistent with a putative role in FSHD, several functional studies of the FRG1 protein have shown it to have a role in both angiogenesis and muscle development by utilising quite different biochemical functions, i.e. alternative RNA splicing and actin bundling (Gabellini et al 2006;van Koningsbruggen et al 2007;Hanel et al 2009;Wuebbles et al 2009;Liu et al 2010;Sun et al 2011). Furthermore, a recent analysis of myoblasts isolated from affected muscle of a transgenic mouse overexpressing FRG1 reported a significant loss of cell proliferation and an increased doubling time not observed in unaffected muscle .…”

Section: Epigenetic Mechanisms Involved In Fshdmentioning

confidence: 87%

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

et al. 2011

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Facioscapulohumeral muscular dystrophy (FS HD) is the third most common muscular dystrophy after the dystrophinopathies and myotonic dystrophy and is associated with a typical pattern of muscle weakness. Most patients with FSHD carry a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35 and present with 1-10 repeats whereas non-affected individuals possess 11-150 repeats. An almost identical repeat array is present at 10q26 and the high sequence identity between these two arrays can cause difficulties in molecular diagnosis. Each 3.3-kb D4Z4 unit contains a DUX4 (double homeobox 4) gene that, among others, is activated upon contraction of the 4q35 repeat array due to the induction of chromatin remodelling of the 4qter region. A number of 4q subtelomeric sequence variants are now recognised, although FSHD only occurs in association with three 'permissive' haplotypes, each of which is associated with a polyadenylation signal located immediately distal of the last D4Z4 unit. The resulting poly-A tail appears to stabilise DUX4 mRNAs transcribed from this most distal D4Z4 unit in FSHD muscle cells. Synthesis of both the DUX4 transcripts and protein in FSHD muscle cells induces significant cell toxicity. DUX4 is a transcription factor that may target several genes which results in a deregulation cascade which inhibits myogenesis, sensitises cells to oxidative stress and induces muscle atrophy, thus recapitulating many of the key molecular features of FSHD.

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Muscular dystrophy candidate gene FRG1 is critical for muscle development

Cited by 46 publications

References 21 publications

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Facioscapulohumeral Muscular Dystrophy: From Clinical Data to Molecular Genetics and Return

Facioscapulohumeral muscular dystrophy region gene-1 (FRG-1) is an actin-bundling protein associated with muscle-attachment sites

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

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