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Facioscapulohumeral Muscular Dystrophy

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ABSTRACT

Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression of the array, and possibly the surrounding 4q35 region, allowing misexpression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. The less common form of the disease, FSHD2, results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele, also leading to the derepression of DUX4, further supporting a central role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a major focus of current investigation. Misexpression of other genes at the 4q35 locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also been implicated as disease modifiers, leading to several competing disease models. In this review, we describe recent advances in understanding the pathophysiology of FSHD, including the application of MRI as a research and diagnostic tool, the genetic and epigenetic disruptions associated with the disease, and the molecular basis of FSHD. We discuss how these advances are leading to the emergence of new approaches to enable development of FSHD therapeutics. © 2017 American Physiological Society. Compr Physiol 7:1229‐1279, 2017.

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Figure 1. Figure 1. FSHD clinical pathology. (A) FSHD subject showing left‐right asymmetry of scapular winging, courtesy of the FSH Society. (B) FSHD subject showing left‐right asymmetry of muscle loss in the lower legs, courtesy of Romana Vysatova and the FSH Society. (C and D) Trichrome‐stained biopsies isolated from the biceps of an unaffected (C) or FSHD affected (D) subjects showing characteristic muscle pathology. Images courtesy of Kathryn Wagner of the Wellstone Center for FSHD and Kennedy Krieger Institute, Johns Hopkins School of Medicine, http://wellstone.umassmed.edu/histology_images/gallery/.
Figure 2. Figure 2. FSHD diagnostic workflow. The workflow steps in the genetic diagnosis of FSHD1 and FSHD2. Detailed descriptions of the molecular assays associated with each step are provided in the text. Image courtesy of Steven Moore, Wellstone Muscular Dystrophy Cooperative Research Center, University of Iowa. http://www.healthcare.uiowa.edu/path_handbook/requisitions/FSHD1&2req.pdf.
Figure 3. Figure 3. Whole‐body MRI evaluation of muscle of FSHD subjects. (A) Heat map of fat infiltration scores of muscles from 13 FSHD subjects, rated on a scale of 0 (white, least infiltrated) to 5 (red, most infiltrated), as assessed by T1‐weighted MRI. (B) An image of a composite whole body MRI. Reproduced with permission from () Leung DG, Carrino JA, Wagner KR, Jacobs MA, Whole‐body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy, Muscle and Nerve 2015 52(4) 512‐520 © 2015 Wiley Periodicals, Inc.
Figure 4. Figure 4. Map of 4q35 D4Z4 repeat locus and the DUX4 transcription unit. (A) The p13E‐11 region and two complete D4Z4 repeat subunits are shown with the terminal partial repeat and pLAM regions of the permissive 4qA allele. Locations of the repeated KpnI site, double homeobox, LSau repeats, and hhspm3 repeats are shown. Adapted from () Jane E. Hewitt, Robert Lyle, Lorraine N. Clark, Elizabeth M. Valleley, Tracy J. Wright, Cisca Wijmenga, Judith C.T. van Deutekom, Fiona Francis, Paul T. Sharpe, Marten Hofker, Rune R. Frants, Robert Williamson, Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy Human Molecular Genetics 1994 3(8):1287‐95 by permission of Oxford University Press. © Oxford University Press. (B) Location of the DUX4 transcriptional unit and the polyadenylation signal in the pLAM region, as well as the DBE sequence. The position of the DBE is indicated and overlaps with the CATT and GC Boxes. Adapted, with permission, from () Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H, Sauvage S, Mattéotti C, van Acker AM, Leo O, Figlewicz D, Barro M, Laoudj‐Chenivesse D, Belayew A, Coppée F, Chen YW, DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1, Proceedings of the National Academy of Sciences USA 2007 104(46):18157‐62. Copyright 2007 National Academy of Sciences.
Figure 5. Figure 5. DUX4 isoforms generated by alternate splicing of the DUX4 transcript. DUX4 protein sequences beginning at the ATG start codon, with the stop codon indicated, and the 3′UTRs shown in orange. The two DUX4‐fl isoforms produce the same protein sequence and differ only in the splicing of the 3′UTR. Sequences were reported in (), and (). Adapted, with permission, from () Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM, Tawil R, Filippova GN, van der Maarel SM, Tapscott SJ, Miller D,Gunder, Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene, PLoS Genetics 2010 28;6(10) under CC BY license. © 2010 Snider et al.
Figure 6. Figure 6. Comparison of 4qA, 4qB, and 10q D4Z4 repeat sequence domains. Locations of the D4Z4 repeats, pLAM sequence, and other repetitive elements are indicated. The number of D4Z4 tandem repeats can vary from a small number (as shown) to over 100. The reverse arrow indicates a truncated D4Z4 repeat in reverse orientation located outside of the array (DUX4c). Adapted, with permission, from () Genomics 2002 79(2) van Geel M, Dickson MC, Beck AF, Bolland DJ, Frants RR, van der Maarel SM, de Jong PJ, Hewitt JE, p210‐7, Genomic Analysis of Human Chromosome 10q and 4q Telomeres Suggests a Common Origin, © Academic Press, with permission from Elsevier.
Figure 7. Figure 7. FSHD candidate genes on chromosome 4q35. Locations of the candidate genes and the DME1 and DME2 myogenic transcription enhancers () are shown. Distances were calculated using the UCSC Genome Browser (http://genome.ucsc.edu/) and constructed with SnapGene Viewer.
Figure 8. Figure 8. DUX4 activation in FSHD myotubes. DUX4 expression was visualized in differentiated 17ABic myogenic cells () using an integrated DUX4‐GFP reporter (). Left panel. GFP fluorescence. Right panel. Phase image with arrows marking the GFP+ myotubes.
Figure 9. Figure 9. DUX4 misexpression dysregulates diverse cellular activities that may contribute to FSHD muscle pathology. DUX4‐fl transcription factor misexpression in skeletal muscle leads to disrupted RNA splicing, nonsense mediated decay (NMD), and protein degradation, possibly causing damaged associated molecular pattern (DAMP) release, which may elicit an immune response to targeted damaged muscles. Changes in gene expression can cause defects in myogenesis and muscle regeneration, apoptosis, and sensitivity to oxidative stress. Also, other DUX4‐fl protein interactions may affect muscle function.
Figure 10. Figure 10. FSHD muscle xenograft model. Left panel. H&E stained section of an FSHD muscle xenograft (Graft) grafted onto host mouse muscle (*). Middle panel. Human muscle fibers identified by anti‐human spectrin immmunostaining. Right panel. DUX4‐fl (arrow) expression detected by PCR in FSHD, but not control xenografts. Adapted, with permission, from () Yuanfan Zhang, Oliver D. King, Fedik Rahimov, Takako I. Jones, Christopher W. Ward, Jaclyn P. Kerr, Naili Liu, Charles P. Emerson, Jr, Louis M. Kunkel, Terence A. Partridge, Kathryn R. Wagner, Human skeletal muscle xenograft as a new preclinical model for muscle disorders, Human Molecular Genetics, 2014 23(12):3180‐8, © Oxford University Press, by permission of Oxford University Press.
Figure 11. Figure 11. Zebrafish DUX4 FSHD model. Zebrafish embryos injected with DUX4‐fl mRNA () showing asymmetrical pathological phenotypes. (A) Uninjected 4‐day postfertilization control embryos. (B) Embryos injected with 0.2pg DUX4‐fl mRNA. (C and D) DUX4‐fl injected embryos showing asymmetric eye (C) and fin (D) development.


Figure 1. FSHD clinical pathology. (A) FSHD subject showing left‐right asymmetry of scapular winging, courtesy of the FSH Society. (B) FSHD subject showing left‐right asymmetry of muscle loss in the lower legs, courtesy of Romana Vysatova and the FSH Society. (C and D) Trichrome‐stained biopsies isolated from the biceps of an unaffected (C) or FSHD affected (D) subjects showing characteristic muscle pathology. Images courtesy of Kathryn Wagner of the Wellstone Center for FSHD and Kennedy Krieger Institute, Johns Hopkins School of Medicine, http://wellstone.umassmed.edu/histology_images/gallery/.


Figure 2. FSHD diagnostic workflow. The workflow steps in the genetic diagnosis of FSHD1 and FSHD2. Detailed descriptions of the molecular assays associated with each step are provided in the text. Image courtesy of Steven Moore, Wellstone Muscular Dystrophy Cooperative Research Center, University of Iowa. http://www.healthcare.uiowa.edu/path_handbook/requisitions/FSHD1&2req.pdf.


Figure 3. Whole‐body MRI evaluation of muscle of FSHD subjects. (A) Heat map of fat infiltration scores of muscles from 13 FSHD subjects, rated on a scale of 0 (white, least infiltrated) to 5 (red, most infiltrated), as assessed by T1‐weighted MRI. (B) An image of a composite whole body MRI. Reproduced with permission from () Leung DG, Carrino JA, Wagner KR, Jacobs MA, Whole‐body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy, Muscle and Nerve 2015 52(4) 512‐520 © 2015 Wiley Periodicals, Inc.


Figure 4. Map of 4q35 D4Z4 repeat locus and the DUX4 transcription unit. (A) The p13E‐11 region and two complete D4Z4 repeat subunits are shown with the terminal partial repeat and pLAM regions of the permissive 4qA allele. Locations of the repeated KpnI site, double homeobox, LSau repeats, and hhspm3 repeats are shown. Adapted from () Jane E. Hewitt, Robert Lyle, Lorraine N. Clark, Elizabeth M. Valleley, Tracy J. Wright, Cisca Wijmenga, Judith C.T. van Deutekom, Fiona Francis, Paul T. Sharpe, Marten Hofker, Rune R. Frants, Robert Williamson, Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy Human Molecular Genetics 1994 3(8):1287‐95 by permission of Oxford University Press. © Oxford University Press. (B) Location of the DUX4 transcriptional unit and the polyadenylation signal in the pLAM region, as well as the DBE sequence. The position of the DBE is indicated and overlaps with the CATT and GC Boxes. Adapted, with permission, from () Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H, Sauvage S, Mattéotti C, van Acker AM, Leo O, Figlewicz D, Barro M, Laoudj‐Chenivesse D, Belayew A, Coppée F, Chen YW, DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1, Proceedings of the National Academy of Sciences USA 2007 104(46):18157‐62. Copyright 2007 National Academy of Sciences.


Figure 5. DUX4 isoforms generated by alternate splicing of the DUX4 transcript. DUX4 protein sequences beginning at the ATG start codon, with the stop codon indicated, and the 3′UTRs shown in orange. The two DUX4‐fl isoforms produce the same protein sequence and differ only in the splicing of the 3′UTR. Sequences were reported in (), and (). Adapted, with permission, from () Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM, Tawil R, Filippova GN, van der Maarel SM, Tapscott SJ, Miller D,Gunder, Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene, PLoS Genetics 2010 28;6(10) under CC BY license. © 2010 Snider et al.


Figure 6. Comparison of 4qA, 4qB, and 10q D4Z4 repeat sequence domains. Locations of the D4Z4 repeats, pLAM sequence, and other repetitive elements are indicated. The number of D4Z4 tandem repeats can vary from a small number (as shown) to over 100. The reverse arrow indicates a truncated D4Z4 repeat in reverse orientation located outside of the array (DUX4c). Adapted, with permission, from () Genomics 2002 79(2) van Geel M, Dickson MC, Beck AF, Bolland DJ, Frants RR, van der Maarel SM, de Jong PJ, Hewitt JE, p210‐7, Genomic Analysis of Human Chromosome 10q and 4q Telomeres Suggests a Common Origin, © Academic Press, with permission from Elsevier.


Figure 7. FSHD candidate genes on chromosome 4q35. Locations of the candidate genes and the DME1 and DME2 myogenic transcription enhancers () are shown. Distances were calculated using the UCSC Genome Browser (http://genome.ucsc.edu/) and constructed with SnapGene Viewer.


Figure 8. DUX4 activation in FSHD myotubes. DUX4 expression was visualized in differentiated 17ABic myogenic cells () using an integrated DUX4‐GFP reporter (). Left panel. GFP fluorescence. Right panel. Phase image with arrows marking the GFP+ myotubes.


Figure 9. DUX4 misexpression dysregulates diverse cellular activities that may contribute to FSHD muscle pathology. DUX4‐fl transcription factor misexpression in skeletal muscle leads to disrupted RNA splicing, nonsense mediated decay (NMD), and protein degradation, possibly causing damaged associated molecular pattern (DAMP) release, which may elicit an immune response to targeted damaged muscles. Changes in gene expression can cause defects in myogenesis and muscle regeneration, apoptosis, and sensitivity to oxidative stress. Also, other DUX4‐fl protein interactions may affect muscle function.


Figure 10. FSHD muscle xenograft model. Left panel. H&E stained section of an FSHD muscle xenograft (Graft) grafted onto host mouse muscle (*). Middle panel. Human muscle fibers identified by anti‐human spectrin immmunostaining. Right panel. DUX4‐fl (arrow) expression detected by PCR in FSHD, but not control xenografts. Adapted, with permission, from () Yuanfan Zhang, Oliver D. King, Fedik Rahimov, Takako I. Jones, Christopher W. Ward, Jaclyn P. Kerr, Naili Liu, Charles P. Emerson, Jr, Louis M. Kunkel, Terence A. Partridge, Kathryn R. Wagner, Human skeletal muscle xenograft as a new preclinical model for muscle disorders, Human Molecular Genetics, 2014 23(12):3180‐8, © Oxford University Press, by permission of Oxford University Press.


Figure 11. Zebrafish DUX4 FSHD model. Zebrafish embryos injected with DUX4‐fl mRNA () showing asymmetrical pathological phenotypes. (A) Uninjected 4‐day postfertilization control embryos. (B) Embryos injected with 0.2pg DUX4‐fl mRNA. (C and D) DUX4‐fl injected embryos showing asymmetric eye (C) and fin (D) development.
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https://www.fshsociety.org

Teaching Material

 

Didactic Synopsis

This review is intended as a guide for graduate students, postdoctoral fellows, and clinical and basic researchers, to the complexities of facioscapulohumeral muscular dystrophy at the clinical, physiological, genetic, epigenetic, molecular, and biochemical levels, and will demonstrate how recent discoveries have become the basis for development of therapeutics to treat this devastating disease. Specific teaching points include:

  1. A clinical and physiological description of FSHD.
    1. Subjects show asymmetrical and progressive loss of muscle strength, muscle mass, and replacement with fat and connective tissue in selected muscle groups.
    2. Whole body imaging is being used to evaluate and study progression of disease pathology.
    3. Immunity and inflammation play a role in muscle pathology.
    4. Clinical severity is highly variable, ranging from infantile to late adult age of onset.
  2. FSHD is a genetic disease with a complex etiology.
    1. FSHD1 disease is associated with deletions and hypomethylation of the D4Z4 repeated DNA sequence array on Chromosome 4.
    2. FSHD2 is associated with mutations in the epigenetic regulatory gene, SMCHD1, that leads to hypomethylation of D4Z4 repeats and clinical disease that is indistinguishable from FSHD1.
    3. Development of FSHD1 and FSHD2 requires a 4qA permissive allele and particular SSLPs.
    4. FSHD1 and FSHD2 are associated with de-repression and low frequency misexpression of the long isoform of the DUX4 gene from the terminal D4Z4 repeat, causing toxicity and muscle fiber death.
    5. Modifier genes likely modulate D4Z4 hypomethylation and DUX4 muscle toxicity.
  3. Epigenetic regulation is a key a disease mechanism.
    1. Expression of DUX4 is regulated by a number of epigenetic protein complexes and RNAs.
    2. DUX4 expression is associated with loss of DNA methylation.
    3. Mutations in epigenetic regulators such as SMCHD1 and DNMT3B act as disease modifiers.
  4. DUX4 protein activity causes cellular pathology.
    1. DUX4 is a well-characterized transcription factor that regulates germline genes.
    2. DUX4 misexpression in muscle induces p53-dependent apoptosis.
    3. DUX4 misexpression in muscle disrupts multiple cellular functions.
    4. DUX4 transcriptional targets are misexpressed in FSHD muscle and are being used as disease biomarkers for therapeutic development studies.
  5. Multiple regulatory genes in addition to DUX4 have been proposed as FSHD disease genes and/or genetic modifiers
    1. Additional FSHD disease genes and disease modifiers include FRG1, FRG2, and FAT1.
  6. Cellular and animal models of FSHD disease have been developed for investigations of disease pathology and therapeutic development.
    1. There is no rodent FSHD model, as DUX4 is a primate specific gene.
    2. Family and subject-derived muscle cell repositories have been established to provide biomarterials to the FSHD research community.
    3. Several DUX4-inducible cell and mouse models have been developed.
    4. Vertebrate and invertebrate models have been developed to investigate alternative candidate FSHD genes, including FRG1, FRG2, and FAT1.
    5. Humanized mouse models have been developed for testing FSHD therapeutics.
  7. Pre-clinical development of FSHD therapeutics is an active area of academic and industry research.
    1. DUX4- and FRG1-targeting siRNA/PMO based approaches have been developed to inhibit the expression and functions of FSHD candidate genes.
    2. Several small molecules have been identified that inhibit or suppress DUX4 muscle toxicity.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. FSHD clinical pathology. (A and B) Demonstrate characteristic muscle wasting and asymmetry in FSHD. Muscle loss and/or scapular winging can be seen in the left side of both subjects, while the right side remains unaffected. Images courtesy of Romana Vysatova and the FSH Society. C and Ddemonstrate the typical histology of muscle biopsies taken from an unaffected (C) and an affected (D) subject. Images courtesy of Kathryn Wagner of the Wellstone Center for FSHD and Kennedy Krieger Institute, Johns Hopkins School of Medicine, http://wellstone.umassmed.edu/histology_images/gallery/.

Figure 2. FSHD diagnostic workflow. This workflow chart demonstrates the steps used in diagnosing a subject with FSHD1 or FSHD2. Image courtesy of Steven Moore, Wellstone Muscular Dystrophy Cooperative Research Center, University of Iowa. http://www.healthcare.uiowa.edu/path_handbook/requisitions/FSHD1&2req.pdf.

Figure 3. Whole-body MRI evaluation of muscle of FSHD subjects. (A) T1 MRI can be used to evaluate the involvement of individual muscles in FSHD subjects and assign them a severity score. (B) A representative composite whole-body MRI. Reproduced with permission from Leung DG, Carrino JA, Wagner KR, Jacobs MA, Whole-body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy, Muscle and Nerve 2015 52(4) 512-520 © 2015 Wiley Periodicals, Inc.

Figure 4. Map of 4q35 D4Z4 repeat locus and the DUX4 transcription unit. (A) An illustration of the final two complete and one partial D4Z4 repeats and their flanking regions is shown. The positions of notable genetic elements (discussed in the text) are indicated. Adapted, with permission, from Jane E. Hewitt, Robert Lyle, Lorraine N. Clark, Elizabeth M. Valleley, Tracy J. Wright, Cisca Wijmenga, Judith C.T. van Deutekom, Fiona Francis, Paul T. Sharpe, Marten Hofker, Rune R. Frants, Robert Williamson, Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy Human Molecular Genetics 1994 3(8):1287-95 by permission of Oxford University Press. © Oxford University Press. (B) The position of the DUX4 gene within the final repeated element is shown. Adapted, with permission, from Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H, Sauvage S, Mattéotti C, van Acker AM, Leo O, Figlewicz D, Barro M, Laoudj-Chenivesse D, Belayew A, Coppée F, Chen YW, DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1, Proceedings of the National Academy of Sciences USA 2007 104(46):18157-62. Copyright 2007 National Academy of Sciences.

Figure 5. DUX4 isoforms generated by alternate splicing of the DUX4 transcript. Alternate splicing produces 3 DUX4 isoforms in muscle cells. Two of the isoforms produce the same protein, while the third produces a truncated version of the protein. Sequences were reported in (55), and (218). Adapted, with permission, from Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM, Tawil R, Filippova GN, van der Maarel SM, Tapscott SJ, Miller D,Gunder, Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene, PLoS Genetics 2010 28;6(10) under CC BY license. © 2010 Snider et al.

Figure 6. Comparison of 4qA, 4qB, and 10q D4Z4 repeat sequence domains. The 4qA and the 4qB haplotypes have different rearrangements of several genetic elements, as shown. The 10q telomere has a very similar arrangement to the 4qA allele. Adapted, with permission, from Genomics 2002 79(2) van Geel M, Dickson MC, Beck AF, Bolland DJ, Frants RR, van der Maarel SM, de Jong PJ, Hewitt JE, p210-7, Genomic Analysis of Human Chromosome 10q and 4q Telomeres Suggests a Common Origin, © Academic Press, with permission from Elsevier.

Figure 7. FSHD candidate genes on chromosome 4q35. Several of the alternate FSHD candidate/modifier genes are located at 4q35, raising the possibility that epigenetic effects caused by loss of D4Z4 repeats may affect their expression. Distances were calculated using the UCSC Genome Browser (http://genome.ucsc.edu/) and constructed with SnapGene Viewer.

Figure 8. DUX4 activation in FSHD myotubes. Left. A GFP reporter construct (199) demonstrates that DUX4 protein can spread to many nuclei in the same myotube. Right. A phase contrast of view of the same cells, with the location of GFP+ cells indicated with arrows.

Figure 9. DUX4 misexpression dysregulates diverse cellular activities that may contribute to FSHD muscle pathology. A summary of the biochemical pathways that DUX4 protein disrupts, possibly leading to pathology.

Figure 10. FSHD Muscle Xenograft Model. Left panel. FSHD muscle (Graft) engrafted onto mouse muscle (*) Center panel. Human-specific spectrin immunostaining of an engrafted FSHD muscle. Right. DUX4-fl can be detected in FSHD xenografts (arrow). Adapted, with permission, from Yuanfan Zhang, Oliver D. King, Fedik Rahimov, Takako I. Jones, Christopher W. Ward, Jaclyn P. Kerr, Naili Liu, Charles P. Emerson, Jr, Louis M. Kunkel, Terence A. Partridge, Kathryn R. Wagner, Human skeletal muscle xenograft as a new preclinical model for muscle disorders, Human Molecular Genetics, 2014 23(12):3180-8, © Oxford University Press, by permission of Oxford University Press.

Figure 11. Zebrafish DUX4 FSHD model. A zebrafish model for DUX4-fl-mediated pathology (161). Uninjected (A) or DUX4-fl injected (B) zebrafish embryos. DUX4-fl injected zebrafish show developmental abnormalities. (C and D) Close-up view of DUX4-fl injected embryos showing asymmetric eye (C) and fin (D) development (arrows).


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Alec M. DeSimone, Anna Pakula, Angela Lek, Charles P. Emerson. Facioscapulohumeral Muscular Dystrophy. Compr Physiol 2017, 7: 1229-1279. doi: 10.1002/cphy.c160039