Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Facioscapulohumeral Muscular Dystrophy

Alec M. DeSimone, Anna Pakula, Angela Lek, Charles P. Emerson

10.1002/cphy.c160039

Source: Volume 7, Issue 4, October 2017

Published online: September 2017

Full Article on Wiley Online Library



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.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


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 (145) 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 (91) 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 (55) 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 (55), and (217). Adapted, with permission, from (218) 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 (259) 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 (92) 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 (104) using an integrated DUX4‐GFP reporter (198). 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 (302) 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 (161) 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 (145) 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 (91) 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 (55) 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 (55), and (217). Adapted, with permission, from (218) 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 (259) 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 (92) 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 (104) using an integrated DUX4‐GFP reporter (198). 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 (302) 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 (161) 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.
References
 1. Altherr MR , Bengtsson U , Markovich RP , Winokur ST . Efforts toward understanding the molecular basis of facioscapulohumeral muscular dystrophy. Muscle Nerve 18: S32‐S38, 1995.
 2. Angelov D , Bondarenko VA , Almagro S , Menoni H , Mongélard F , Hans F , Mietton F , Studitsky VM , Hamiche A , Dimitrov S , Bouvet P . Nucleolin is a histone chaperone with FACT‐like activity and assists remodeling of nucleosomes. EMBO J 25: 1669‐1679, 2006.
 3. Ansseau E , Eidahl JO , Lancelot C , Tassin A , Matteotti C , Yip C , Liu J , Leroy B , Hubeau C , Gerbaux C , Cloet S , Wauters A , Zorbo S , Meyer P , Pirson I , Laoudj‐Chenivesse D , Wattiez R , Harper SQ , Belayew A , CoppÈe F . Homologous transcription factors DUX4 and DUX4c associate with cytoplasmic proteins during muscle differentiation. PLoS One 11: e0146893, 2016.
 4. Ansseau E , Laoudj‐Chenivesse D , Marcowycz A , Sauvage S , Barro M , Tassin A , Mattéotti C , van Acker A , Leroy A , Leclercq I , Leo O , Figlewicz D , Belayew A , Coppée F . G.P.9 06 characterization of the DUX4c gene located within a repeated element close to the FSHD locus. Neuromuscul Disord 16: 712, 2006.
 5. Ansseau E , Laoudj‐Chenivesse D , Marcowycz A , Tassin A , Vanderplanck C , Sauvage S , Barro M , Mahieu I , Leroy A , Leclercq I , Mainfroid V , Figlewicz D , Mouly V , Butler‐Browne G , Belayew A , CoppÈe F . DUX4c is up‐regulated in FSHD. It induces the MYF5 protein and human myoblast proliferation. PLoS One 4: e7482, 2009.
 6. Arahata K , Ishihara T , Fukunaga H , Orimo S , Lee JH , Goto K , Nonaka I . Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): Immunocytochemical and genetic analyses. Muscle Nerve 18: S56‐S66, 1995.
 7. Arashiro P , Eisenberg I , Kho AT , Cerqueira AMP , Canovas M , Silva HCA , Pavanello RCM , Verjovski‐Almeida S , Kunkel LM , Zatz M . Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers. Proc Natl Acad Sci U S A 106: 6220‐6225, 2009.
 8. Bakker E , Wijmenga C , Vossen RHAM , Padberg GW , Hewitt J , van Der Wielen M , Rasmussen K , Frants RR . The FSHD‐linked locus D4F104S1 (p13E‐11) ON 4q35 has a homologue on 10qter. Muscle Nerve 18: S39‐S44, 1995.
 9. Balog J , Thijssen PE , de Greef JC , Shah B , van Engelen BGM , Yokomori K , Tapscott SJ , Tawil R , van der Maarel SM . Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics 7: 579‐584, 2012.
 10. Balog J , Thijssen PE , Shadle S , Straasheijm KR , van der Vliet PJ , Krom YD , van den Boogaard ML , de Jong A , Lemmers RJLF , Tawil R , Tapscott SJ , van der Maarel SM . Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 10: 1133‐1142, 2015.
 11. Banerji CRS , Knopp P , Moyle LA , Severini S , Orrell RW , Teschendorff AE , Zammit PS . β‐Catenin is central to DUX4‐driven network rewiring in facioscapulohumeral muscular dystrophy. J R Soc Interface 12, 2015.
 12. Barro M , Carnac G , Flavier S , Mercier J , Vassetzky Y , Laoudj‐Chenivesse D . Myoblasts from affected and non‐affected FSHD muscles exhibit morphological differentiation defects. J Cell Mol Med 14: 275‐289, 2010.
 13. Berger J , Currie PD . Zebrafish models flex their muscles to shed light on muscular dystrophies. Disease Models and Mechanisms 5: 726‐732, 2012.
 14. Blewitt ME , Gendrel A‐V , Pang Z , Sparrow DB , Whitelaw N , Craig JM , Apedaile A , Hilton DJ , Dunwoodie SL , Brockdorff N , Kay GF , Whitelaw E . SmcHD1, containing a structural‐maintenance‐of‐chromosomes hinge domain, has a critical role in X inactivation. Nat Genet 40: 663‐669, 2008.
 15. Blewitt ME , Vickaryous NK , Hemley SJ , Ashe A , Bruxner TJ , Preis JI , Arkell R , Whitelaw E . An N‐ethyl‐N‐nitrosourea screen for genes involved in variegation in the mouse. Proc Natl Acad Sci U S A 102: 7629‐7634, 2005.
 16. Block GJ , Narayanan D , Amell AM , Petek LM , Davidson KC , Bird TD , Tawil R , Moon RT , Miller DG . Wnt/β‐catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells. Hum Mol Genet 22: 4661‐4672, 2013.
 17. Block GJ , Petek LM , Narayanan D , Amell AM , Moore JM , Rabaia NA , Tyler A , van der Maarel SM , Tawil R , Filippova GN , Miller DG . Asymmetric bidirectional transcription from the FSHD‐causing D4Z4 array modulates DUX4 production. PLoS One 7: e35532, 2012.
 18. Bodega B , Ramirez GDC , Grasser F , Cheli S , Brunelli S , Mora M , Meneveri R , Marozzi A , Mueller S , Battaglioli E , Ginelli E . 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. BMC Biol 7: 1‐15, 2009.
 19. Bortolanza S , Nonis A , Sanvito F , Maciotta S , Sitia G , Wei J , Torrente Y , Di Serio C , Chamberlain JR , Gabellini D . AAV6‐mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy. Mol Ther 19: 2055‐2064, 2011.
 20. Bosnakovski D , Choi SH , Strasser JM , Toso EA , Walters MA , Kyba M . High‐throughput screening identifies inhibitors of DUX4‐induced myoblast toxicity. Skeletal Muscle 4: 1‐11, 2014.
 21. Bosnakovski D , Lamb S , Simsek T , Xu Z , Belayew A , Perlingeiro R , Kyba M . DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation. Exp Neurol 214: 87‐96, 2008.
 22. Bosnakovski D , Xu Z , Ji Gang E , Galindo CL , Liu M , Simsek T , Garner HR , Agha‐Mohammadi S , Tassin A , Coppée F , Belayew A , Perlingeiro RR , Kyba M . An isogenetic myoblast expression screen identifies DUX4‐mediated FSHD‐associated molecular pathologies. EMBO J 27: 2766‐2779, 2008.
 23. Bou Saada Y , Dib C , Dmitriev P , Hamade A , Carnac G , Laoudj‐Chenivesse D , Lipinski M , Vassetzky YS . Facioscapulohumeral dystrophy myoblasts efficiently repair moderate levels of oxidative DNA damage. Histochem Cell Biol 145: 475‐483, 2016.
 24. Bouju S , Piétu G , Le Cunff M , Cros N , Malzac P , Pellissier J‐F , Pons F , Léger J‐J , Auffray C , Dechesne CA . Exclusion of muscle specific actinin‐associated LIM protein (ALP) gene from 4q35 facioscapulohumeral muscular dystrophy (FSHD) candidate genes. Neuromuscul Disord 9: 3‐10, 1999.
 25. Brooke MH , Griggs RC , Mendell JR , Fenichel GM , Shumate JB , Pellegrino RJ . Clinical trial in duchenne dystrophy. I. The design of the protocol. Muscle Nerve 4: 186‐197, 1981.
 26. Broucqsault N , Morere J , Gaillard M‐C , Dumonceaux J , Torrents J , Salort‐Campana E , Maues De Paula A , Bartoli M , Fernandez C , Chesnais AL , Ferreboeuf M , Sarda L , Dufour H , Desnuelle C , Attarian S , Levy N , Nguyen K , Magdinier F , Roche S . Dysregulation of 4q35‐ and muscle‐specific genes in fetuses with a short D4Z4 array linked to facio‐scapulo‐humeral dystrophy. Hum Mol Genet 22: 4206‐4214, 2013.
 27. Brouwer OF , Padberg GW , Ruys CJ , Brand R , de Laat JA , Grote JJ . Hearing loss in facioscapulohumeral muscular dystrophy. Neurology 41: 1878‐1881, 1991.
 28. Butz M , Koch MC , Muller‐Felber W , Lemmers RJLF , Maarel SM , Schreiber H . Facioscapulohumeral muscular dystrophy. Phenotype‐genotype correlation in patients with borderline D4Z4 repeat numbers. J Neurol 250: 932‐937, 2003.
 29. Cabianca Daphne S , Casa V , Bodega B , Xynos A , Ginelli E , Tanaka Y , Gabellini D . A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell 149: 819‐831, 2012.
 30. Cacurri S , Piazzo N , Deidda G , Vigneti E , Galluzzi G , Colantoni L , Merico B , Ricci E , Felicetti L . Sequence homology between 4qter and 10qter loci facilitates the instability of subtelomeric KpnI repeat units implicated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 63: 181‐190, 1998.
 31. Calandra P , Cascino I , Lemmers RJLF , Galluzzi G , Teveroni E , Monforte M , Tasca G , Ricci E , Moretti F , van der Maarel SM , Deidda G . Allele‐specific DNA hypomethylation characterises FSHD1 and FSHD2. J Med Genet 53: 348‐355, 2016.
 32. Caruso N , Herberth Bz , Bartoli M , Puppo F , Dumonceaux J , Zimmermann A , Denadai S , LebossÈ M , Roche S , Geng L , Magdinier F , Attarian S , Bernard R , Maina F , Levy N , Helmbacher F . Deregulation of the protocadherin gene FAT1 alters muscle shapes: Implications for the pathogenesis of facioscapulohumeral dystrophy. PLoS Genet 9: e1003550, 2013.
 33. Celegato B , Capitanio D , Pescatori M , Romualdi C , Pacchioni B , Cagnin S , Viganò A , Colantoni L , Begum S , Ricci E , Wait R , Lanfranchi G , Gelfi C . Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD‐dependent genes. Proteomics 6: 5303‐5321, 2006.
 34. Cheli S , FranÁois S , Bodega B , Ferrari F , Tenedini E , Roncaglia E , Ferrari S , Ginelli E , Meneveri R . Expression profiling of FSHD‐1 and FSHD‐2 cells during myogenic differentiation evidences common and distinctive gene dysregulation patterns. PLoS One 6: e20966, 2011.
 35. Chen JCJ , King OD , Zhang Y , Clayton NP , Spencer C , Wentworth BM , Emerson CP, Jr. , Wagner KR . Morpholino‐mediated knockdown of DUX4 toward facioscapulohumeral muscular dystrophy therapeutics. Mol Ther 24: 1405‐1411, 2016.
 36. Chen SC , Frett E , Marx J , Bosnakovski D , Reed X , Kyba M , Kennedy BK . Decreased proliferation kinetics of mouse myoblasts overexpressing FRG1 . PLoS One 6: e19780, 2011.
 37. Chen TH , Lai YH , Lee PL , Hsu JH , Goto K , Hayashi YK , Nishino I , Lin CW , Shih HH , Huang CC , Liang WC , Wang WF , Jong YJ . Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment. Neuromuscul Disord 23: 298‐305, 2013.
 38. Choi SH , Gearhart MD , Cui Z , Bosnakovski D , Kim M , Schennum N , Kyba M . DUX4 recruits p300/CBP through its C‐terminus and induces global H3K27 acetylation changes. Nucleic Acids Res 44: 5161‐5173, 2016.
 39. Ciani L , Patel A , Allen ND , ffrench‐Constant C . Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 23: 3575‐3582, 2003.
 40. Clapp J , Mitchell LM , Bolland DJ , Fantes J , Corcoran AE , Scotting PJ , Armour JAL , Hewitt JE . Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 81: 264‐279, 2007.
 41. Clark LN , Koehler U , Ward DC , Wienberg J , Hewitt JE . Analysis of the organisation and localisation of the FSHD‐associated tandem array in primates: Implications for the origin and evolution of the 3.3 kb repeat family. Chromosoma 105: 180‐189, 1996.
 42. Corona ED , Jacquelin D , Gatica L , Rosa AL . Multiple protein domains contribute to nuclear import and cell toxicity of DUX4, a candidate pathogenic protein for facioscapulohumeral muscular dystrophy. PLoS One 8: e75614, 2013.
 43. Cowling BS , McGrath MJ , Nguyen M‐A , Cottle DL , Kee AJ , Brown S , Schessl J , Zou Y , Joya J , Bönnemann CG , Hardeman EC , Mitchell CA . Identification of FHL1 as a regulator of skeletal muscle mass: Implications for human myopathy. J Cell Biol 183: 1033‐1048, 2008.
 44. D'Antona G , Brocca L , Pansarasa O , Rinaldi C , Tupler R , Bottinelli R . Structural and functional alterations of muscle fibres in the novel mouse model of facioscapulohumeral muscular dystrophy. J Physiol 584: 997‐1009, 2007.
 45. Dandapat A , Bosnakovski D , Hartweck LM , Arpke RW , Baltgalvis KA , Vang D , Baik J , Darabi R , Perlingeiro R , Hamra FK , Gupta K , Lowe DA , Kyba M . Dominant lethal pathologies in male mice engineered to contain an X‐linked DUX4 transgene. Cell Rep 8: 1484‐1496, 2014.
 46. Dandapat A , Perrin BJ , Cabelka C , Razzoli M , Ervasti JM , Bartolomucci A , Lowe DA , Kyba M . High frequency hearing loss and hyperactivity in DUX4 transgenic mice. PLoS One 11: e0151467, 2016.
 47. de Greef JC , Lemmers RJLF , Camaño P , Day JW , Sacconi S , Dunand M , van Engelen BGM , Kiuru‐Enari S , Padberg GW , Rosa AL , Desnuelle C , Spuler S , Tarnopolsky M , Venance SL , Frants RR , van der Maarel SM , Tawil R . Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology 75: 1548‐1554, 2010.
 48. de Greef JC , Lemmers RJLF , van Engelen BGM , Sacconi S , Venance SL , Frants RR , Tawil R , van der Maarel SM . Common epigenetic changes of D4Z4 in contraction‐dependent and contraction‐independent FSHD. Hum Mutat 30: 1449‐1459, 2009.
 49. de Greef JC , Wohlgemuth M , Chan OA , Hansson KB , Smeets D , Frants RR , Weemaes CM , Padberg GW , van der Maarel SM . Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD. Neurology 69: 1018‐1026, 2007.
 50. de la Kethulle de Ryhove L , Ansseau E , Nachtegael C , Pieters K , Vanderplanck C , Geens M , Sermon K , Wilton SD , Coppée F , Lagneaux L , Belayew A . The role of D4Z4‐encoded proteins in the osteogenic differentiation of mesenchymal stromal cells isolated from bone marrow. Stem Cells Dev 24: 2674‐2686, 2015.
 51. Deak KL , Lemmers RJLF , Stajich JM , Klooster R , Tawil R , Frants RR , Speer MC , van der Maarel SM , Gilbert JR . Genotype‐phenotype study in an FSHD family with a proximal deletion encompassing p13E‐11 and D4Z4. Neurology 68: 578‐582, 2007.
 52. Deenen JCW , Arnts H , van der Maarel SM , Padberg GW , Verschuuren JJGM , Bakker E , Weinreich SS , Verbeek ALM , van Engelen BGM . Population‐based incidence and prevalence of facioscapulohumeral dystrophy. Neurology 83: 1056‐1059, 2014.
 53. Deidda G , Cacurri S , Piazzo N , Felicetti L . Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD). J Med Genet 33, 1996.
 54. Dib C , Saada YB , Dmitriev P , Richon C , Dessen P , Laoudj‐Chenivesse D , Carnac G , Lipinski M , Vassetzky YS . Correction of the FSHD myoblast differentiation defect by fusion with healthy myoblasts. J Cell Physiol 231: 62‐71, 2016.
 55. 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 Y‐W . DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci U S A 104: 18157‐18162, 2007.
 56. Dmitriev P , Stankevicins L , Ansseau E , Petrov A , Barat A , Dessen P , Robert T , Turki A , Lazar V , Labourer E , Belayew A , Carnac G , Laoudj‐Chenivesse D , Lipinski M , Vassetzky YS . Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. J Biol Chem 288: 34989‐35002, 2013.
 57. Du J , Johnson LM , Jacobsen SE , Patel DJ . DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol 16: 519‐532, 2015.
 58. Dubowitz V , Brooke MH . Muscle Biopsy; a Modern Approach. London: Saunders, 1973.
 59. Eichinger K , Heatwole C , Heininger S , Stinson N , Matichak Stock C , Grosmann C , Wagner KR , Tawil R , Statland JM , and on behalf of the FCTRN. Validity of the six minute walk test in facioscapulohumeral muscular dystrophy. Muscle Nerve 55: 333‐337, 2016.
 60. Eisenberg I , Eran A , Nishino I , Moggio M , Lamperti C , Amato AA , Lidov HG , Kang PB , North KN , Mitrani‐Rosenbaum S , Flanigan KM , Neely LA , Whitney D , Beggs AH , Kohane IS , Kunkel LM . Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci U S A 104: 17016‐17021, 2007.
 61. Faustmann PM , Farahati J , Rupilius B , Dux R , Koch MC , Reiners C . Cardiac involvement in facio‐scapulo‐humeral muscular dystrophy: A family study using Thallium‐201 single‐photon‐emission‐computed tomography. J Neurol Sci 144: 59‐63, 1996.
 62. Feeney SJ , McGrath MJ , Sriratana A , Gehrig SM , Lynch GS , D?Arcy CE , Price JT , McLean CA , Tupler R , Mitchell CA . FHL1 reduces dystrophy in transgenic mice overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1) . PLoS One 10: e0117665, 2015.
 63. Feng Q , Snider L , Jagannathan S , Tawil R , van der Maarel SM , Tapscott SJ , Bradley RK . A feedback loop between nonsense‐mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. eLife 4: e04996, 2015.
 64. Ferreboeuf M , Mariot V , Bessières B , Vasiljevic A , Attié‐Bitach T , Collardeau S , Morere J , Roche S , Magdinier F , Robin‐Ducellier J , Rameau P , Whalen S , Desnuelle C , Sacconi S , Mouly V , Butler‐Browne G , Dumonceaux J . DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Hum Mol Genet 23: 171‐181, 2014.
 65. Ferri G , Huichalaf CH , Caccia R , Gabellini D . Direct interplay between two candidate genes in FSHD muscular dystrophy. Hum Mol Genet 24: 1256‐1266, 2015.
 66. Friedman SD , Poliachik SL , Carter GT , Budech CB , Bird TD , Shaw DWW . The magnetic resonance imaging spectrum of facioscapulohumeral muscular dystrophy. Muscle Nerve 45: 500‐506, 2012.
 67. Friedman SD , Poliachik SL , Otto RK , Carter GT , Budech CB , Bird TD , Miller DG , Shaw DWW . Longitudinal features of stir bright signal in FSHD1. Muscle Nerve 49: 257‐260, 2014.
 68. Frisullo G , Frusciante R , Nociti V , Tasca G , Renna R , Iorio R , Patanella AK , Iannaccone E , Marti A , Rossi M , Bianco A , Monforte M , Tonali PA , Mirabella M , Batocchi AP , Ricci E . CD8+ T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol 31: 155‐166, 2011.
 69. Funakoshi M , Goto K , Arahata K . Epilepsy and mental retardation in a subset of early onset 4q35‐facioscapulohumeral muscular dystrophy. Neurology 50: 1791‐1794, 1998.
 70. Gabellini D , D'Antona G , Moggio M , Prelle A , Zecca C , Adami R , Angeletti B , Ciscato P , Pellegrino MA , Bottinelli R , Green MR , Tupler R . Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature 439: 973‐977, 2006.
 71. Gabellini D , Green MR , Tupler R . Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110: 339‐348, 2002.
 72. Gabriëls J , Beckers MC , Ding H , De Vriese A , Plaisance S , van der Maarel SM , Padberg GW , Frants RR , Hewitt JE , Collen D , Belayew A . Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236: 25‐32, 1999.
 73. Gaillard M‐C , Roche S , Dion C , Tasmadjian A , Bouget G , Salort‐Campana E , Vovan C , Chaix C , Broucqsault N , Morere J , Puppo F , Bartoli M , Levy N , Bernard R , Attarian S , Nguyen K , Magdinier F . Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers. Neurology 83: 733‐742, 2014.
 74. Ganesh A , Kaliki S , Shields CL . Coats‐like retinopathy in an infant with preclinical facioscapulohumeral dystrophy. J Aapos 16: 204‐206, 2012.
 75. Gartel AL , Tyner AL . The role of the cyclin‐dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1: 639‐649, 2002.
 76. Gehring WJ , Affolter M , Burglin T . Homeodomain proteins. Annu Rev Biochem 63: 487‐526, 1994.
 77. Geisler SJ , Paro R . Trithorax and Polycomb group‐dependent regulation: A tale of opposing activities. Development 142: 2876‐2887, 2015.
 78. Gendrel A‐V , Apedaile A , Coker H , Termanis A , Zvetkova I , Godwin J , Tang YA , Huntley D , Montana G , Taylor S , Giannoulatou E , Heard E , Stancheva I , Brockdorff N . Smchd1‐dependent and ‐independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev Cell 23: 265‐279, 2012.
 79. Geng Linda N , Yao Z , Snider L , Fong Abraham P , Cech Jennifer N , Young Janet M , van der Maarel Silvere M , Ruzzo Walter L , Gentleman Robert C , Tawil R , Tapscott Stephen J . DUX4 activates germline genes, retroelements, and immune mediators: Implications for facioscapulohumeral dystrophy. Dev Cell 22: 38‐51, 2012.
 80. Gerevini S , Scarlato M , Maggi L , Cava M , Caliendo G , Pasanisi B , Falini A , Previtali SC , Morandi L . Muscle MRI findings in facioscapulohumeral muscular dystrophy. Eur Radiol 26: 693‐705, 2016.
 81. Gilbert JR , Stajich JM , Wall S , Carter SC , Qiu H , Vance JM , Stewart CS , Speer MC , Pufky J , Yamaoka LH , Rozear M , Samson F , Fardeau M , Roses AD , Pericak‐Vance MA . Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD). Am J Hum Genet 53: 401‐408, 1993.
 82. Goto K , Lee JEH , Matsuda C , Hirabayashi K , Kojo T , Nakamura A , Mitsunaga Y , Furukawa T , Sahashi KO , Arahata K . DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: Clinical correlations. Neuromuscul Disord 5: 201‐208, 1995.
 83. Grewal PK , Carim Todd L , van der Maarel S , Frants RR , Hewitt JE . FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Gene 216: 13‐19, 1998.
 84. Griggs RC , Tawil R , McDermott M , Forrester J , Figlewicz D , Weiffenbach B . Monozygotic twins with facioscapulohumeral dystrophy (FSHD): Implications for genotype/phenotype correlation. Muscle Nerve 18: S50‐S55, 1995.
 85. Hanel ML , Sun C‐YJ , Jones TI , Long SW , Zanotti S , Milner D , Jones PL . Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein. Differentiation 81: 107‐118, 2011.
 86. Hanel ML , Wuebbles RD , Jones PL . Muscular dystrophy candidate gene FRG1 is critical for muscle development. Dev Dyn 238: 1502‐1512, 2009.
 87. Harafuji N , Schneiderat P , Walter MC , Chen Y‐W . miR‐411 is up‐regulated in FSHD myoblasts and suppresses myogenic factors. Orphanet J Rare Dis 8: 1‐10, 2013.
 88. Haraguchi Y , Chung AB , Torroni A , Stepien G , Shoffner JM , Wasmuth JJ , Costigan DA , Polak M , Altherr MR , Winokur ST , Wallace DC . Genetic mapping of human heart‐skeletal muscle adenine nucleotide translocator and its relationship to the facioscapulohumeral muscular dystrophy locus. Genomics 16: 479‐485, 1993.
 89. Hartweck LM , Anderson LJ , Lemmers RJ , Dandapat A , Toso EA , Dalton JC , Tawil R , Day JW , van der Maarel SM , Kyba M . A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology 80: 392‐399, 2013.
 90. Hewitt JE , Clark LN , Ivens A , Williamson R . Structure and sequence of the human homeobox gene HOX7. Genomics 11: 670‐678, 1991.
 91. Hewitt JE , Lyle R , Clark LN , Valleley EM , Wright TJ , Wijmenga C , van Deutekom JCT , Francis F , Sharpe PT , Hofker M , Frants RR , Williamson R . Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystropothhy. Hum Mol Genet 3: 1287‐1295, 1994.
 92. Himeda CL , Debarnot C , Homma S , Beermann ML , Miller JB , Jones PL , Jones TI . Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy‐associated DUX4 gene. Mol Cell Biol 34: 1942‐1955, 2014.
 93. Himeda CL , Jones TI , Jones PL . CRISPR/dCas9‐mediated transcriptional inhibition ameliorates the epigenetic dysregulation at D4Z4 and represses DUX4‐fl in FSH muscular dystrophy. Mol Ther 24: 527‐535, 2016.
 94. Homma S , Beermann ML , Boyce FM , Miller JB . Expression of FSHD‐related DUX4‐FL alters proteostasis and induces TDP‐43 aggregation. Ann Clin Transl Neurol 2: 151‐166, 2015.
 95. Homma S , Chen JCJ , Rahimov F , Beermann ML , Hanger K , Bibat GM , Wagner KR , Kunkel LM , Emerson CP, Jr. , Miller JB . A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: Family, disease and cell function. Eur J Hum Genet 20: 404‐410, 2012.
 96. Huichalaf C , Micheloni S , Ferri G , Caccia R , Gabellini D . DNA methylation analysis of the macrosatellite repeat associated with FSHD muscular dystrophy at single nucleotide level. PLoS One 9: e115278, 2015.
 97. Jagannathan S , Shadle SC , Resnick R , Snider L , Tawil RN , van der Maarel SM , Bradley RK , Tapscott SJ . Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Hum Mol Genet 25(20): 4419‐4431, 2016.
 98. Janssen B , Voet N , Geurts A , van Engelen B , Heerschap A . Quantitative MRI reveals decelerated fatty infiltration in muscles of active FSHD patients. Neurology 86: 1700‐1707, 2016.
 99. Janssen BH , Pillen S , Voet NB , Heerschap A , van Engelen BG , van Alfen N . Quantitative muscle ultrasound versus quantitative magnetic resonance imaging in facioscapulohumeral dystrophy. Muscle Nerve 50: 968‐975, 2014.
 100. Janssen BH , Voet NB , Nabuurs CI , Kan HE , de Rooy JW , Geurts AC , Padberg GW , van Engelen BG , Heerschap A . Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration. PLoS One 9: e85416, 2014.
 101. Jardine PE , Koch MC , Lunt PW , Maynard J , Bathke KD , Harper PS , Upadhyaya M . De novo facioscapulohumeral muscular dystrophy defined by DNA probe p13E‐11 (D4F104S1). Arch Dis Child 71: 221‐227, 1994.
 102. Jiang G , Yang F , van Overveld PGM , Vedanarayanan V , van der Maarel S , Ehrlich M . Testing the position‐effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet 12: 2909‐2921, 2003.
 103. Jones PA. Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet 13: 484‐492, 2012.
 104. Jones TI , Chen JCJ , Rahimov F , Homma S , Arashiro P , Beermann ML , King OD , Miller JB , Kunkel LM , Emerson CP , Wagner KR , Jones PL . Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: Evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet 21: 4419‐4430, 2012.
 105. Jones TI , King OD , Himeda CL , Homma S , Chen JCJ , Beermann ML , Yan C , Emerson CP , Miller JB , Wagner KR , Jones PL . Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics 7: 1‐22, 2015.
 106. Jones TI , Parilla M , Jones PL . Transgenic Drosophila for investigating DUX4 and FRG1, two genes associated with facioscapulohumeral muscular dystrophy (FSHD). PLoS One 11: e0150938, 2016.
 107. Jones TI , Yan C , Sapp PC , McKenna‐Yasek D , Kang PB , Quinn C , Salameh JS , King OD , Jones PL . Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing. Clin Epigenetics 6: 1‐16, 2014.
 108. Jordan B , Eger K , Koesling S , Zierz S . Camptocormia phenotype of FSHD: A clinical and MRI study on six patients. J Neurol 258: 866‐873, 2011.
 109. Jurica MS , Licklider LJ , Gygi SR , Grigorieff N , Moore MJ . Purification and characterization of native spliceosomes suitable for three‐dimensional structural analysis. RNA 8: 426‐439, 2002.
 110. Kan HE , Klomp DWJ , Wohlgemuth M , van Loosbroek‐Wagemans I , van Engelen BGM , Padberg GW , Heerschap A . Only fat infiltrated muscles in resting lower leg of FSHD patients show disturbed energy metabolism. NMR Biomed 23: 563‐568, 2010.
 111. Katoh M. Function and cancer genomics of FAT family genes. Int J Oncol 41: 1913‐1918, 2012.
 112. Kemp GJ , Meyerspeer M , Moser E . Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: A quantitative review. NMR Biomed 20: 555‐565, 2007.
 113. Kim E , Rich J , Karoutas A , Tarlykov P , Cochet E , Malysheva D , Mamchaoui K , Ogryzko V , Pirozhkova I . ZNF555 protein binds to transcriptional activator site of 4qA allele and ANT1: Potential implication in Facioscapulohumeral dystrophy. Nucleic Acids Res 43: 8227‐8242, 2015.
 114. Klooster R , Straasheijm K , Shah B , Sowden J , Frants R , Thornton C , Tawil R , van der Maarel S . Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level. Eur J Hum Genet 17: 1615‐1624, 2009.
 115. Knopp P , Krom YD , Banerji CRS , Panamarova M , Moyle LA , den Hamer B , van der Maarel SM , Zammit PS . DUX4 induces a transcriptome more characteristic of a less‐differentiated cell state and inhibits myogenesis. J Cell Sci 129: 3816‐3831, 2016.
 116. Kole R , Krainer AR , Altman S . RNA therapeutics: Beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11: 125‐140, 2012.
 117. Kottlors M , Kress W , Meng G , Glocker FX . Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome. Muscle Nerve 42: 273‐275, 2010.
 118. Kowaljow V , Marcowycz A , Ansseau E , Conde CB , Sauvage S , Mattéotti C , Arias C , Corona ED , Nuñez NG , Leo O , Wattiez R , Figlewicz D , Laoudj‐Chenivesse D , Belayew A , Coppée F , Rosa AL . The DUX4 gene at the FSHD1A locus encodes a pro‐apoptotic protein. Neuromuscul Disord 17: 611‐623, 2007.
 119. Krom YD , Dumonceaux J , Mamchaoui K , den Hamer B , Mariot V , Negroni E , Geng LN , Martin N , Tawil R , Tapscott SJ , van Engelen BGM , Mouly V , Butler‐Browne GS , van der Maarel SM . Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: A cellular model for FSHD. Am J Pathol 181: 1387‐1401, 2012.
 120. Krom YD , Thijssen PE , Young JM , den Hamer B , Balog J , Yao Z , Maves L , Snider L , Knopp P , Zammit PS , Rijkers T , van Engelen BGM , Padberg GW , Frants RR , Tawil R , Tapscott SJ , van der Maarel SM . Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. PLoS Genet 9: e1003415, 2013.
 121. Krysko DV , Agostinis P , Krysko O , Garg AD , Bachert C , Lambrecht BN , Vandenabeele P . Emerging role of damage‐associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32: 157‐164, 2011.
 122. Krysko O , Love Aaes T , Bachert C , Vandenabeele P , Krysko DV . Many faces of DAMPs in cancer therapy. Cell Death Dis 4: e631, 2013.
 123. Lamperti C , Fabbri G , Vercelli L , D'Amico R , Frusciante R , Bonifazi E , Fiorillo C , Borsato C , Cao M , Servida M , Greco F , Di Leo R , Volpi L , Manzoli C , Cudia P , Pastorello E , Ricciardi L , Siciliano G , Galluzzi G , Rodolico C , Santoro L , Tomelleri G , Angelini C , Ricci E , Palmucci L , Moggio M , Tupler R . A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score. Muscle Nerve 42: 213‐217, 2010.
 124. Land WG . The role of damage‐associated molecular patterns in human diseases: Part I—Promoting inflammation and immunity. Sultan Qaboos Univ Med J 15: e9‐e21, 2015.
 125. Landoyzy L , Dejerine J . De la myopathie atrophique progressive (myopathie héréditaire, débutant dans l'enfance par la face, sans altération du système nerveux). Comptes rendus de l'Académie des sciences, Paris 98: 53–55, 1884.
 126. Laoudj‐Chenivesse D , Carnac G , Bisbal C , Hugon G , Bouillot S , Desnuelle C , Vassetzky Y , Fernandez A . Increased levels of adenine nucleotide translocator 1 protein and response to oxidative stress are early events in facioscapulohumeral muscular dystrophy muscle. J Mol Med 83: 216‐224, 2004.
 127. Larsen M , Rost S , El Hajj N , Ferbert A , Deschauer M , Walter MC , Schoser B , Tacik P , Kress W , Muller CR . Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet 23: 808‐816, 2015.
 128. Lassche S , Stienen GJ , Irving TC , van der Maarel SM , Voermans NC , Padberg GW , Granzier H , van Engelen BG , Ottenheijm CA . Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy. Neurology 80: 733‐737, 2013.
 129. Lee GD , Chen VM , Barnes AC , Goldman DR , Duker JS . Retinal telangiectasis detected during a vision screening examination in a child with hearing loss led to the diagnosis of facioscapulohumeral muscular dystrophy. J Aapos 18: 303‐305, 2014.
 130. Lee JH , Goto K , Matsuda C , Arahata K . Characterization of a tandemly repeated 3.3‐kb Kpnl unit in the facioscapulohumeral muscular dystrophy (FSHD) gene region on chromosome 4q35. Muscle Nerve 18: S6‐S13, 1995.
 131. Leidenroth A , Hewitt JE . A family history of DUX4: phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUXgene. BMC Evol Biol 10: 1‐13, 2010.
 132. Lek A , Rahimov F , Jones PL , Kunkel LM . Emerging preclinical animal models for FSHD. Trends Mol Med 21: 295‐306, 2015.
 133. Lemmers RJ , van der Maarel SM , van Deutekom JC , van der Wielen MJ , Deidda G , Dauwerse HG , Hewitt J , Hofker M , Bakker E , Padberg GW , Frants RR . Inter‐ and intrachromosomal sub‐telomeric rearrangements on 4q35: Implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis. Hum Mol Genet 7, 1998.
 134. Lemmers RJ , van der Wielen MJ , Bakker E , Padberg GW , Frants RR , van der Maarel SM . Somatic mosaicism in FSHD often goes undetected. Ann Neurol 55: 845‐850, 2004.
 135. Lemmers RJFL , Wohlgemuth M , Frants RR , Padberg GW , Morava E , van der Maarel SM . Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet 75: 1124‐1130, 2004.
 136. Lemmers RJL , de Kievit P , van Geel M , van der Wielen MJ , Bakker E , Padberg GW , Frants RR , van der Maarel SM . Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Ann Neurol 50: 816‐819, 2001.
 137. Lemmers RJLF , de Kievit P , Sandkuijl L , Padberg GW , van Ommen G‐JB , Frants RR , van der Maarel SM . Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet 32: 235‐236, 2002.
 138. Lemmers RJLF , Goeman JJ , van der Vliet PJ , van Nieuwenhuizen MP , Balog J , Vos‐Versteeg M , Camano P , Ramos Arroyo MA , Jerico I , Rogers MT , Miller DG , Upadhyaya M , Verschuuren JJGM , Lopez de Munain Arregui A , van Engelen BGM , Padberg GW , Sacconi S , Tawil R , Tapscott SJ , Bakker B , van der Maarel SM . Inter‐individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24: 659‐669, 2015.
 139. Lemmers RJLF , Osborn M , Haaf T , Rogers M , Frants RR , Padberg GW , Cooper DN , van der Maarel SM , Upadhyaya M . D4F104S1 deletion in facioscapulohumeral muscular dystrophy: Phenotype, size, and detection. Neurology 61: 178‐183, 2003.
 140. Lemmers RJLF , Tawil R , Petek LM , Balog J , Block GJ , Santen GWE , Amell AM , van der Vliet PJ , Almomani R , Straasheijm KR , Krom YD , Klooster R , Sun Y , den Dunnen JT , Helmer Q , Donlin‐Smith CM , Padberg GW , van Engelen BGM , de Greef JC , Aartsma‐Rus AM , Frants RR , de Visser M , Desnuelle C , Sacconi S , Filippova GN , Bakker B , Bamshad MJ , Tapscott SJ , Miller DG , van der Maarel SM . Digenic inheritance of an SMCHD1 mutation and an FSHD‐permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44: 1370‐1374, 2012.
 141. Lemmers RJLF , van den Boogaard ML , van der Vliet PJ , Donlin‐Smith CM , Nations SP , Ruivenkamp CAL , Heard P , Bakker B , Tapscott S , Cody JD , Tawil R , van der Maarel SM . Hemizygosity for SMCHD1 in facioscapulohumeral muscular dystrophy type 2: Consequences for 18p deletion syndrome. Hum Mutat 36: 679‐683, 2015.
 142. Lemmers RJLF , van der Vliet PJ , Klooster R , Sacconi S , Camaño P , Dauwerse JG , Snider L , Straasheijm KR , Jan van Ommen G , Padberg GW , Miller DG , Tapscott SJ , Tawil R , Frants RR , van der Maarel SM . A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329: 1650‐1653, 2010.
 143. Lemmers RJLF , van der Vliet PJ , van der Gaag KJ , Zuniga S , Frants RR , de Knijff P , van der Maarel SM . Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution. Am J Hum Genet 86: 364‐377, 2010.
 144. Lemmers RJLF , Wohlgemuth M , van der Gaag KJ , van der Vliet PJ , van Teijlingen CMM , de Knijff P , Padberg GW , Frants RR , van der Maarel SM . Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet 81: 884‐894, 2007.
 145. Leung DG , Carrino JA , Wagner KR , Jacobs MA . Whole‐body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy. Muscle Nerve 52: 512‐520, 2015.
 146. Lim J‐W , Snider L , Yao Z , Tawil R , Van Der Maarel SM , Rigo F , Bennett CF , Filippova GN , Tapscott SJ . DICER/AGO‐dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD. Hum Mol Genet 24: 4817‐4828, 2015.
 147. Lin M‐Y , Nonaka I . Facioscapulohumeral muscular dystrophy: Muscle fiber type analysis with particular reference to small angular fibers. Brain Dev 13: 331‐338, 1991.
 148. Liu Q , Jones TI , Tang VW , Brieher WM , Jones PL . Facioscapulohumeral muscular dystrophy region gene‐1 (FRG‐1) is an actin‐bundling protein associated with muscle‐attachment sites. J Cell Sci 123: 1116‐1123, 2010.
 149. Lunt PW . 44th ENMC International Workshop: Facioscapulohumeral Muscular Dystrophy: Molecular Studies: 19–21 July 1996, Naarden, The Netherlands. Neuromuscul Disord 8: 126‐130, 1998.
 150. Lunt PW , Harper PS . Genetic counselling in facioscapulohumeral muscular dystrophy. J Med Genet 28: 655‐664, 1991.
 151. Lyle R , Wright TJ , Clark LN , Hewitt JE . The FSHD‐associated repeat, D4Z4, is a member of a dispersed family of homeobox‐containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes. Genomics 28: 389‐397, 1995.
 152. Mariot V , Roche S , Hourdé C , Portilho D , Sacconi S , Puppo F , Duguez S , Rameau P , Caruso N , Delezoide A‐L , Desnuelle C , Bessières B , Collardeau S , Feasson L , Maisonobe T , Magdinier F , Helmbacher F , Butler‐Browne G , Mouly V , Dumonceaux J . Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. Ann Neurol 78: 387‐400, 2015.
 153. Marsollier A‐C , Ciszewski L , Mariot V , Popplewell L , Voit T , Dickson G , Dumonceaux J . Antisense targeting of 3′ end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: A new gene‐silencing approach. Hum Mol Genet 25: 1468‐1478, 2016.
 154. Martin SJ. Cell death and inflammation: The case for IL‐1 family cytokines as the canonical DAMPs of the immune system. FEBS J 283: 2599‐2615, 2016.
 155. Masny PS , Bengtsson U , Chung S‐A , Martin JH , van Engelen B , van der Maarel SM , Winokur ST . Localization of 4q35.2 to the nuclear periphery: Is FSHD a nuclear envelope disease? Hum Mol Genet 13: 1857‐1871, 2004.
 156. Masny PS , Chan OYA , de Greef JC , Bengtsson U , Ehrlich M , Tawil R , Lock LF , Hewitt JE , Stocksdale J , Martin JH , van der Maarel SM , Winokur ST . Analysis of allele‐specific RNA transcription in FSHD by RNA‐DNA FISH in single myonuclei. Eur J Hum Genet 18: 448‐456, 2010.
 157. Mathews KD , Mills KA , Bosch EP , Ionasescu VV , Wiles KR , Buetow KH , Murray JC . Linkage localization of facioscapulohumeral muscular dystrophy (FSHD) in 4q35. Am J Hum Genet 51: 428‐431, 1992.
 158. May DA , Disler DG , Jones EA , Balkissoon AA , Manaster BJ . Abnormal signal intensity in skeletal muscle at MR imaging: Patterns, pearls, and pitfalls. RadioGraphics 20: S295‐S315, 2000.
 159. McDonald CM , Henricson EK , Han JJ , Abresch RT , Nicorici A , Atkinson L , Elfring GL , Reha A , Miller LL . The 6‐minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve 42: 966‐974, 2010.
 160. Mills KA , Buetow KH , Xu Y , Ritty TM , Mathews KD , Bodrug SE , Wijmenga C , Balazs I , Murray JC . Genetic and physical mapping on chromosome 4 narrows the localization of the gene for facioscapulohumeral muscular dystrophy (FSHD). Am J Hum Genet 51: 432‐439, 1992.
 161. Mitsuhashi H , Mitsuhashi S , Lynn‐Jones T , Kawahara G , Kunkel LM . Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum Mol Genet 22: 568‐577, 2013.
 162. Mitsuhashi S , Boyden SE , Estrella EA , Jones TI , Rahimov F , Yu TW , Darras BT , Amato AA , Folkerth RD , Jones PL , Kunkel LM , Kang PB . Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2. Neuromuscul Disord 23: 975‐980, 2013.
 163. Mul K , Lassche S , Voermans NC , Padberg GW , Horlings CG , van Engelen BG . What's in a name? The clinical features of facioscapulohumeral muscular dystrophy. Pract Neurol 16: 201‐207, 2016.
 164. Mul K , van den Boogaard ML , van der Maarel SM , van Engelen BG . Integrating clinical and genetic observations in facioscapulohumeral muscular dystrophy. Curr Opin Neurol 29: 606‐613, 2016.
 165. Neguembor MV , Xynos A , Onorati MC , Caccia R , Bortolanza S , Godio C , Pistoni M , Corona DF , Schotta G , Gabellini D . FSHD muscular dystrophy region gene 1 binds Suv4‐20h1 histone methyltransferase and impairs myogenesis. J Mol Cell Biol 5: 294‐307, 2013.
 166. Nikolic A , Ricci G , Sera F , Bucci E , Govi M , Mele F , Rossi M , Ruggiero L , Vercelli L , Ravaglia S , Brisca G , Fiorillo C , Villa L , Maggi L , Cao M , D'Amico MC , Siciliano G , Antonini G , Santoro L , Mongini T , Moggio M , Morandi L , Pegoraro E , Angelini C , Di Muzio A , Rodolico C , Tomelleri G , Grazia D'Angelo M , Bruno C , Berardinelli A , Tupler R . Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: Experience of the FSHD Italian National Registry. BMJ Open 6: e007798, 2016.
 167. Olsen DB , Gideon P , Jeppesen TD , Vissing J . Leg muscle involvement in facioscapulohumeral muscular dystrophy assessed by MRI. J Neurol 253: 1437‐1441, 2006.
 168. Osborne RJ , Welle S , Venance SL , Thornton CA , Tawil R . Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy. Neurology 68: 569‐577, 2007.
 169. Ottaviani A , Rival‐Gervier S , Boussouar A , Foerster AM , Rondier D , Sacconi S , Desnuelle C , Gilson E , Magdinier F . The D4Z4 macrosatellite repeat acts as a CTCF and A‐type lamins‐dependent insulator in facio‐scapulo‐humeral dystrophy. PLoS Genet 5: e1000394, 2009.
 170. Padberg GWAM. Facioscapulohumeral disease. Thesis Leiden, the Netherlands University of Leiden, 1982.
 171. Padua L , Aprile I , Frusciante R , Iannaccone E , Rossi M , Renna R , Messina S , Frasca G , Ricci E . Quality of life and pain in patients with facioscapulohumeral muscular dystrophy. Muscle Nerve 40: 200‐205, 2009.
 172. Pakula A , Schneider J , Janke J , Zacharias U , Schulz H , Habner N , M‰hler A , Spuler A , Spuler S , Carlier P , Boschmann M . Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD‐1). PLoS One 8: e73573, 2013.
 173. Pandey S , Khawaja H , Chen Y‐W . Culture conditions affect expression of DUX4 in FSHD myoblasts. Molecules 20: 8304, 2015.
 174. Pandey SN , Cabotage J , Shi R , Dixit M , Sutherland M , Liu J , Muger S , Harper SQ , Nagaraju K , Chen Y‐W . Conditional over‐expression of PITX1 causes skeletal muscle dystrophy in mice. Biol Open 1: 629‐639, 2012.
 175. Pandey SN , Lee Y‐C , Yokota T , Chen Y‐W . Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Mol Ther 22: 390‐396, 2014.
 176. Panteghini M. Enzyme and muscle diseases. Curr Opin Rheumatol 7: 469‐474, 1995.
 177. Pantoja M , Ruohola‐Baker H . Drosophila as a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy. Rare Diseases 1: e24995, 2013.
 178. Park HJ , Hong JM , Lee JH , Lee HS , Shin HY , Kim SM , Ki CS , Choi YC . Low D4Z4 copy number and gender difference in Korean patients with facioscapulohumeral muscular dystrophy type 1. Neuromuscul Disord 25: 859‐864, 2015.
 179. Passerieux E , Hayot M , Jaussent A , Carnac G , Gouzi F , Pillard F , Picot M‐C , Böcker K , Hugon G , Pincemail J , Defraigne JO , Verrips T , Mercier J , Laoudj‐Chenivesse D . Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: A double‐blind randomized controlled clinical trial. Free Radic Biol Med 81: 158‐169, 2015.
 180. Pastorello E , Cao M , Trevisan CP . Atypical onset in a series of 122 cases with facioscapulohumeral muscular dystrophy. Clin Neurol Neurosurg 114: 230‐234, 2012.
 181. Paternostro‐Sluga T , Grim‐Stieger M , Posch M , Schuhfried O , Vacariu G , Mittermaier C , Bittner C , Fialka‐Moser V . Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 40: 665‐671, 2008.
 182. Petek LM , Rickard AM , Budech C , Poliachik SL , Shaw D , Ferguson MR , Tawil R , Friedman SD , Miller DG . A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 26: 405‐413, 2016.
 183. Petrov A , Allinne J , Pirozhkova I , Laoudj D , Lipinski M , Vassetzky YS . A nuclear matrix attachment site in the 4q35 locus has an enhancer‐blocking activity in vivo: Implications for the facio‐scapulo‐humeral dystrophy. Genome Res 18: 39‐45, 2008.
 184. Petrov A , Pirozhkova I , Carnac G , Laoudj D , Lipinski M , Vassetzky YS . Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts. Proc Natl Acad Sci U S A 103: 6982‐6987, 2006.
 185. Pillen S , Arts IMP , Zwarts MJ . Muscle ultrasound in neuromuscular disorders. Muscle Nerve 37: 679‐693, 2008.
 186. Pirozhkova I , Petrov A , Dmitriev P , Laoudj D , Lipinski M , Vassetzky Y . A functional role for 4qA/B in the structural rearrangement of the 4q35 region and in the regulation of FRG1 and ANT1 in facioscapulohumeral dystrophy. PLoS One 3: e3389, 2008.
 187. Pistoni M , Shiue L , Cline MS , Bortolanza S , Neguembor MV , Xynos A , Ares M, Jr. , Gabellini D . Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). PLoS Genet 9: e1003186, 2013.
 188. Pradhan S. Poly‐Hill sign in facioscapulohumeral dystrophy. Muscle Nerve 25: 754‐755, 2002.
 189. Puppo F , Dionnet E , Gaillard M‐C , Gaildrat P , Castro C , Vovan C , Bertaux K , Bernard R , Attarian S , Goto K , Nishino I , Hayashi Y , Magdinier F , Krahn M , Helmbacher F , Bartoli M , Lévy N . Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy‐like phenotype. Hum Mutat 36: 443‐453, 2015.
 190. Quarantelli M , Lanzillo R , Del Vecchio W , Mollica C , Prinster A , Iadicicco L , Iodice V , Santoro L , Salvatore M . Modifications of brain tissue volumes in facioscapulohumeral dystrophy. Neuroimage 32: 1237‐1242, 2006.
 191. Rahimov F , King OD , Leung DG , Bibat GM , Emerson CP , Kunkel LM , Wagner KR . Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers. Proc Natl Acad Sci U S A 109: 16234‐16239, 2012.
 192. Rappsilber J , Ryder U , Lamond AI , Mann M . Large‐scale proteomic analysis of the human spliceosome. Genome Res 12: 1231‐1245, 2002.
 193. Ratti A , Buratti E . Physiological functions and pathobiology of TDP‐43 and FUS/TLS proteins. J Neurochem 138: 95‐111, 2016.
 194. Regula JU , Jestaedt L , Jende F , Bartsch A , Meinck H‐M , Weber M‐A . Clinical muscle testing compared with whole‐body magnetic resonance imaging in facio‐scapulo‐humeral muscular dystrophy. Clin Neuroradiol 26: 1‐11, 2015.
 195. Ricci E , Galluzzi G , Deidda G , Cacurri S , Colantoni L , Merico B , Piazzo N , Servidei S , Vigneti E , Pasceri V , Silvestri G , Mirabella M , Mangiola F , Tonali P , Felicetti L . Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol 45: 751‐757, 1999.
 196. Ricci G , Ruggiero L , Vercelli L , Sera F , Nikolic A , Govi M , Mele F , Daolio J , Angelini C , Antonini G , Berardinelli A , Bucci E , Cao M , D'Amico MC , D'Angelo G , Di Muzio A , Filosto M , Maggi L , Moggio M , Mongini T , Morandi L , Pegoraro E , Rodolico C , Santoro L , Siciliano G , Tomelleri G , Villa L , Tupler R . A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes. J Neurol 263: 1204‐1214, 2016.
 197. Ricci G , Scionti I , Ali G , Volpi L , Zampa V , Fanin M , Angelini C , Politano L , Tupler R , Siciliano G . Rippling muscle disease and facioscapulohumeral dystrophy‐like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for “double trouble” overlapping syndromes. Neuromuscul Disord 22: 534‐540, 2012.
 198. Rickard AM , Petek LM , Miller DG . Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. Hum Mol Genet 24: 5901‐5914, 2015.
 199. Rijken NHM , van der Kooi EL , Hendriks JCM , van Asseldonk RJGP , Padberg GW , Geurts ACH , van Engelen BGM . Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement. Neuromuscul Disord 24: 1087‐1096, 2014.
 200. Rijkers T , Deidda G , van Koningsbrugge S , van Geel M , Lemmers R , van Deutekom JCT , Figlewicz D , Hewitt J , Padberg G , Frants R , van der Maarel SM . FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients. J Med Genet 41: 826‐836, 2004.
 201. Robin JD , Ludlow AT , Batten K , Gaillard M‐C , Stadler G , Magdinier F , Wright WE , Shay JW . SORBS2 transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy. Genome Res 25: 1781‐1790, 2015.
 202. Rutkove SB . Electrical impedance myography: Background, current state, and future directions. Muscle Nerve 40: 936‐946, 2009.
 203. Sacconi S , Lemmers Richard JLF , Balog J , van der Vliet Patrick J , Lahaut P , van Nieuwenhuizen Merlijn P , Straasheijm Kirsten R , Debipersad Rashmie D , Vos‐Versteeg M , Salviati L , Casarin A , Pegoraro E , Tawil R , Bakker E , Tapscott Stephen J , Desnuelle C , van der Maarel Silvère M . The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93: 744‐751, 2013.
 204. Sakellariou P , O'Neill A , Mueller AL , Stadler G , Wright WE , Roche JA , Bloch RJ . Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts. Skeletal Muscle 6: 1‐14, 2016.
 205. Salort‐Campana E , Nguyen K , Lévy N , Pouget J , Attarian S . Clinical and molecular diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) in 2012. Rev Neurol (Paris) 169: 573‐582, 2013.
 206. Sancisi V , Germinario E , Esposito A , Morini E , Peron S , Moggio M , Tomelleri G , Danieli‐Betto D , Tupler R . Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1). Am J Physiol Regul Integr Comp Physiol 306: R124‐R137, 2014.
 207. Sandri M , El Meslemani AH , Sandri C , Schjerling P , Vissing K , Andersen JL , Rossini K , Carraro U , Angelini C . Caspase 3 expression correlates with skeletal muscle apoptosis in Duchenne and facioscapulo human muscular dystrophy. A potential target for pharmacological treatment? J Neuropathol Exp Neurol 60: 302‐312, 2001.
 208. Sarfarazi M , Wijmenga C , Upadhyaya M , Weiffenbach B , Hyser C , Mathews K , Murray J , Gilbert J , Pericak‐Vance M , Lunt P , Frants RR , Jacobsen S , Harper PS , Padberg GW . Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: Combined analysis of an international consortium. Am J Hum Genet 51: 396‐403, 1992.
 209. Schreiber O , Schneiderat P , Kress W , Rautenstrauss B , Senderek J , Schoser B , Walter MC . Facioscapulohumeral muscular dystrophy and Charcot‐Marie‐Tooth neuropathy 1A ‐ evidence for “double trouble” overlapping syndromes. BMC Med Genet 14: 92, 2013.
 210. Scionti I , Fabbri G , Fiorillo C , Ricci G , Greco F , D'Amico R , Termanini A , Vercelli L , Tomelleri G , Cao M , Santoro L , Percesepe A , Tupler R . Facioscapulohumeral muscular dystrophy: New insights from compound heterozygotes and implication for prenatal genetic counselling. J Med Genet 49: 171‐178, 2012.
 211. Scionti I , Greco F , Ricci G , Govi M , Arashiro P , Vercelli L , Berardinelli A , Angelini C , Antonini G , Cao M , Di Muzio A , Moggio M , Morandi L , Ricci E , Rodolico C , Ruggiero L , Santoro L , Siciliano G , Tomelleri G , Trevisan Carlo P , Galluzzi G , Wright W , Zatz M , Tupler R . Large‐scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy. Am J Hum Genet 90: 628‐635, 2012.
 212. Sharer JD. The adenine nucleotide translocase type 1 (ANT1): A new factor in mitochondrial disease. IUBMB Life 57: 607‐614, 2005.
 213. Sharma V , Harafuji N , Belayew A , Chen Y‐W . DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse #c2C12 cells. PLoS One 8: e64691, 2013.
 214. Sharma V , Pandey SN , Khawaja H , Brown KJ , Hathout Y , Chen Y‐W . PARP1 differentially interacts with promoter region of DUX4 gene in FSHD myoblasts. J Genet Syndr Gene Ther 7: 303, 2016.
 215. Shcherbata HR , Yatsenko AS , Patterson L , Sood VD , Nudel U , Yaffe D , Baker D , Ruohola‐Baker H . Dissecting muscle and neuronal disorders in a Drosophila model of muscular dystrophy. EMBO J 26: 481‐493, 2007.
 216. Skalsky AJ , Abresch RT , Han JJ , Shin CS , McDonald CM . The relationship between regional body composition and quantitative strength in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 18: 873‐880, 2008.
 217. Snider L , Asawachaicharn A , Tyler AE , Geng LN , Petek LM , Maves L , Miller DG , Lemmers RJLF , Winokur ST , Tawil R , van der Maarel SM , Filippova GN , Tapscott SJ . RNA transcripts, miRNA‐sized fragments and proteins produced from D4Z4 units: New candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet 18: 2414‐2430, 2009.
 218. Snider L , Geng LN , Lemmers RJLF , Kyba M , Ware CB , Nelson AM , Tawil R , Filippova GN , van der Maarel SM , Tapscott SJ , Miller DG . Facioscapulohumeral dystrophy: Incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181, 2010.
 219. Stadler G , Chen JC , Wagner K , Robin JD , Shay JW , Emerson CP, Jr. , Wright WE . Establishment of clonal myogenic cell lines from severely affected dystrophic muscles ‐ CDK4 maintains the myogenic population. Skeletal Muscle 1: 1‐10, 2011.
 220. Stadler G , Rahimov F , King OD , Chen JCJ , Robin JD , Wagner KR , Shay JW , Emerson CP , Wright WE . Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Nat Struct Mol Biol 20: 671‐678, 2013.
 221. Statland J , Tawil R . Facioscapulohumeral muscular dystrophy. Neurol Clin 32: 721‐728, 2014.
 222. Statland JM , Donlin‐Smith CM , Tapscott SJ , Lemmers RJLF , van der Maarel SM , Tawil R . Milder phenotype in facioscapulohumeral dystrophy with 7–10 residual D4Z4 repeats. Neurology 85: 2147‐2150, 2015.
 223. Statland JM , Heatwole C , Eichinger K , Dilek N , Martens WB , Tawil R . Electrical impedance myography in facioscapulohumeral muscular dystrophy. Muscle Nerve 54: 696‐701, 2016.
 224. Statland JM , Odrzywolski KJ , Shah B , Henderson D , Fricke AF , van der Maarel SM , Tapscott SJ , Tawil R . Immunohistochemical characterization of facioscapulohumeral muscular dystrophy muscle biopsies. J Neuromuscul Dis 2: 291‐299, 2015.
 225. Statland JM , Sacconi S , Farmakidis C , Donlin‐Smith CM , Chung M , Tawil R . Coats syndrome in facioscapulohumeral dystrophy type 1: Frequency and D4Z4 contraction size. Neurology 80: 1247‐1250, 2013.
 226. Statland JM , Shah B , Henderson D , Van Der Maarel S , Tapscott SJ , Tawil R . Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies. Muscle Nerve 52: 521‐526, 2015.
 227. Stubgen JP. Facioscapulohumeral muscular dystrophy. A quantitative electromyographic study. Electromyogr Clin Neurophysiol 47: 175‐182, 2007.
 228. Sun C‐YJ , van Koningsbruggen S , Long SW , Straasheijm K , Klooster R , Jones TI , Bellini M , Levesque L , Brieher WM , van der Maarel SM , Jones PL . Facioscapulohumeral muscular dystrophy region gene 1 is a dynamic RNA‐associated and actin‐bundling protein. J Mol Biol 411: 397‐416, 2011.
 229. Tam R , Smith KP , Lawrence JB . The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres. J Cell Biol 167: 269‐279, 2004.
 230. Tasca G , Monforte M , Iannaccone E , Laschena F , Ottaviani P , Leoncini E , Boccia S , Galluzzi G , Pelliccioni M , Masciullo M , Frusciante R , Mercuri E , Ricci E . Upper girdle imaging in facioscapulohumeral muscular dystrophy. PLoS One 9: e100292, 2014.
 231. Tasca G , Monforte M , Ottaviani P , Pelliccioni M , Frusciante R , Laschena F , Ricci E . Magnetic resonance imaging in a large cohort of facioscapulohumeral muscular dystrophy patients: Pattern refinement and implications for clinical trials. Ann Neurol 79(5): 854‐864, 2016.
 232. Tasca G , Pescatori M , Monforte M , Mirabella M , Iannaccone E , Frusciante R , Cubeddu T , Laschena F , Ottaviani P , Ricci E . Different molecular signatures in magnetic resonance imaging‐staged facioscapulohumeral muscular dystrophy muscles. PLoS One 7: e38779, 2012.
 233. Tassin A , Laoudj‐Chenivesse D , Vanderplanck C , Barro M , Charron S , Ansseau E , Chen Y‐W , Mercier J , Coppée F , Belayew A . DUX4 expression in FSHD muscle cells: How could such a rare protein cause a myopathy? J Cell Mol Med 17: 76‐89, 2013.
 234. Tassin A , Leroy B , Laoudj‐Chenivesse D , Wauters A , Vanderplanck C , Le Bihan M‐C , CoppÈe F , Wattiez R , Belayew A . FSHD myotubes with different phenotypes exhibit distinct proteomes. PLoS One 7: e51865, 2012.
 235. Tawil R. Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5: 601‐606, 2008.
 236. Tawil R , Forrester J , Griggs R , Mendell J , Kissel J , McDermott M , King W , Weiffenbach B , Figlewicz D . Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH‐DY Group. Ann Neurol 39: 744‐748, 1996.
 237. Taylor DA , Carroll JE , Smith ME , Johnson MO , Johnston GP , Brooke MH . Facioscapulohumeral dystrophy associated with hearing loss and Coats syndrome. Ann Neurol 12: 395‐398, 1982.
 238. Theodorou DJ , Theodorou SJ , Kakitsubata Y . Skeletal muscle disease: Patterns of MRI appearances. Br J Radiol 85: e1298‐e1308, 2012.
 239. Thijssen PE , Balog J , Yao Z , Pham TP , Tawil R , Tapscott SJ , Van der Maarel SM . DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy. Skeletal Muscle 4: 1‐9, 2014.
 240. Thomas JO , Travers AA . HMG1 and 2, and related ‘architectural’ DNA‐binding proteins. Trends Biochem Sci 26: 167‐174, 2001.
 241. Thomas MJ , Seto E . Unlocking the mechanisms of transcription factor YY1: Are chromatin modifying enzymes the key? Gene 236: 197‐208, 1999.
 242. Tonini MM , Passos‐Bueno MR , Cerqueira A , Matioli SR , Pavanello R , Zatz M . Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 14: 33‐38, 2004.
 243. Trevisan CP , Pastorello E , Tomelleri G , Vercelli L , Bruno C , Scapolan S , Siciliano G , Comacchio F . Facioscapulohumeral muscular dystrophy: Hearing loss and other atypical features of patients with large 4q35 deletions. Eur J Neurol 15: 1353‐1358, 2008.
 244. Tsien F , Sun B , Hopkins NE , Vedanarayanan V , Figlewicz D , Winokur S , Ehrlich M . Methylation of the FSHD syndrome‐linked subtelomeric repeat in normal and FSHD cell cultures and tissues. Mol Genet Metab 74: 322‐331, 2001.
 245. Tsumagari K , Chang S‐C , Lacey M , Baribault C , Chittur SV , Sowden J , Tawil R , Crawford GE , Ehrlich M . Gene expression during normal and FSHD myogenesis. BMC Med Genomics 4: 67‐67, 2011.
 246. Tupler R , Berardinelli A , Barbierato L , Frants R , Hewitt JE , Lanzi G , Maraschio P , Tiepolo L . Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J Med Genet 33: 366‐370, 1996.
 247. Tupler R , Perini G , Pellegrino MA , Green MR . Profound misregulation of muscle‐specific gene expression in facioscapulohumeral muscular dystrophy. Proc Natl Acad Sci U S A 96: 12650‐12654, 1999.
 248. Turki A , Hayot M , Carnac G , Pillard F , Passerieux E , Bommart S , de Mauverger ER , Hugon G , Pincemail J , Pietri S , Lambert K , Belayew A , Vassetzky Y , Juntas Morales R , Mercier J , Laoudj‐Chenivesse D . Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction. Free Radic Biol Med 53: 1068‐1079, 2012.
 249. Tyler FH , Stephens FE . Studies in disorders of muscle. ii. Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family* . Ann Intern Med 32: 640‐660, 1950.
 250. Upadhyaya M , Lunt P , Sarfarazi M , Broadhead W , Farnham J , Harper PS . The mapping of chromosome 4q markers in relation to facioscapulohumeral muscular dystrophy (FSHD). Am J Hum Genet 51: 404‐410, 1992.
 251. Upadhyaya M , Lunt PW , Sarfarazi M , Broadhead W , Daniels J , Owen M , Harper PS . A closely linked DNA marker for facioscapulohumeral disease on chromosome 4q. J Med Genet 28: 665‐671, 1991.
 252. van den Boogaard ML , Jfl Lemmers R , Camano P , van der Vliet PJ , Voermans N , van Engelen BGM , Lopez de Munain A , Tapscott SJ , van der Stoep N , Tawil R , van der Maarel SM . Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. Eur J Hum Genet 24: 78‐85, 2016.
 253. van den Boogaard Marlinde L , Lemmers Richard JLF , Balog J , Wohlgemuth M , Auranen M , Mitsuhashi S , van der Vliet Patrick J , Straasheijm Kirsten R , van den Akker Rob FP , Kriek M , Laurense‐Bik Marlies EY , Raz V , van Ostaijen‐ten Dam Monique M , Hansson Kerstin BM , van der Kooi Elly L , Kiuru‐Enari S , Udd B , van Tol Maarten JD , Nishino I , Tawil R , Tapscott Stephen J , van Engelen Baziel GM , van der Maarel Silvère M . Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy. Am J Hum Genet 98: 1020‐1029, 2016.
 254. van der Maarel SM , Deidda G , Lemmers RJ , van Overveld PG , van der Wielen M , Hewitt JE , Sandkuijl L , Bakker B , van Ommen GJ , Padberg GW , Frants RR . De novo facioscapulohumeral muscular dystrophy: Frequent somatic mosaicism, sex‐dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet 66: 26‐35, 2000.
 255. van der Maarel SM , Deidda G , Lemmers RJLF , van Overveld PGM , van der Wielen M , Hewitt JE , Sandkuijl L , Bakker B , van Ommen G‐JB , Padberg GW , Frants RR . De novo facioscapulohumeral muscular dystrophy: Frequent somatic mosaicism, sex‐dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet 66: 26‐35, 2000.
 256. van Deutekom JCT , Bakker E , Lemmers RJLF , van der Wielen MJR , Bik E , Hofker MH , Padberg GW , Frants RR . Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: Implications for genetic counselling and etiology of FSHD1. Hum Mol Genet 5: 1997‐2003, 1996.
 257. van Deutekom JCT , Lemmers RJLF , Grewal PK , van Geel M , Romberg S , Dauwerse HG , Wright TJ , Padberg GW , Hofker MH , Hewitt JE , Frants RR . Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum Mol Genet 5: 581‐590, 1996.
 258. van Deutekom JCT , Wljmenga C , Tlenhoven EAEV , Gruter A‐M , Hewitt JE , Padberg GW , Ommen G‐JBv , Hofker MH , Fronts RR . FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 2: 2037‐2042, 1993.
 259. van Geel M , Dickson MC , Beck AF , Bolland DJ , Frants RR , van der Maarel SM , de Jong PJ , Hewitt JE . Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin. Genomics 79: 210‐217, 2002.
 260. van Koningsbruggen S , Dirks R , Mommaas A , Onderwater J , Deidda G , Padberg G , Frants R , van der Maarel SM . FRG1P is localised in the nucleolus, Cajal bodies, and speckles. J Med Genet 41: e46‐e46, 2004.
 261. van Koningsbruggen S , Straasheijm KR , Sterrenburg E , Graaf N , Dauwerse HG , Frants RR , Maarel SM . FRG1P‐mediated aggregation of proteins involved in pre‐mRNA processing. Chromosoma 116: 53‐64, 2007.
 262. van Overveld PG , Lemmers RJ , Deidda G , Sandkuijl L , Padberg GW , Frants RR , van Der Maarel SM . Interchromosomal repeat array interactions between chromosomes 4 and 10: A model for subtelomeric plasticity. Hum Mol Genet 9(19): 2879‐2884, 2000.
 263. Van Overveld PGM , Enthoven L , Ricci E , Rossi M , Felicetti L , Jeanpierre M , Winokur ST , Frants RR , Padberg GW , Van Der Maarel SM . Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann Neurol 58: 569‐576, 2005.
 264. van Overveld PGM , Lemmers RJFL , Sandkuijl LA , Enthoven L , Winokur ST , Bakels F , Padberg GW , van Ommen G‐JB , Frants RR , van der Maarel SM . Hypomethylation of D4Z4 in 4q‐linked and non‐4q‐linked facioscapulohumeral muscular dystrophy. Nat Genet 35: 315‐317, 2003.
 265. Vanderplanck C , Ansseau E , Charron S , Stricwant N , Tassin A , Laoudj‐Chenivesse D , Wilton SD , CoppÈe F , Belayew A . The FSHD atrophic myotube phenotype is caused by DUX4 expression. PLoS One 6: e26820, 2011.
 266. Vilquin JT , Marolleau JP , Sacconi S , Garcin I , Lacassagne MN , Robert I , Ternaux B , Bouazza B , Larghero J , Desnuelle C . Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients. Gene Ther 12: 1651‐1662, 2005.
 267. Wallace LM , Garwick SE , Mei W , Belayew A , Coppee F , Ladner KJ , Guttridge D , Yang J , Harper SQ . DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo. Ann Neurol 69: 540‐552, 2011.
 268. Wallace LM , Garwick‐Coppens SE , Tupler R , Harper SQ . RNA interference improves myopathic phenotypes in mice over‐expressing FSHD region gene 1 (FRG1). Mol Ther 19: 2048‐2054, 2011.
 269. Wallace LM , Liu J , Domire JS , Garwick‐Coppens SE , Guckes SM , Mendell JR , Flanigan KM , Harper SQ . RNA interference inhibits DUX4‐induced muscle toxicity in vivo: Implications for a targeted FSHD therapy. Mol Ther 20: 1417‐1423, 2012.
 270. Wang LH , Tawil R . Facioscapulohumeral dystrophy. Curr Neurol Neurosci Rep 16: 66, 2016.
 271. Weiffenbach B , Bagley R , Falls K , Hyser C , Storvick D , Jacobsen SJ , Schultz P , Mendell J , van Dijk KW , Milner ECB , Griggs R . Linkage analyses of five chromosome 4 markers localizes the facioscapulohumeral muscular dystrophy (FSHD) gene to distal 4q35. Am J Hum Genet 51: 416‐423, 1992.
 272. Weiffenbach B , Bagley RG , Falls K , Dubois J , Hyser C , Storvick D , Schultz P , Mendell JR , Millner ECB , Jacobsen SJ , Griggs RC . Framework multipoint map of the long arm of human Chromosome 4 and telomeric localization of the gene for FSHD. Mamm Genome 3: 143‐150, 1992.
 273. Weiffenbach B , Dubois J , Storvick D , Tawil R , Jacobsen SJ , Gilbert J , Wijmenga C , Mendell JR , Winokur S , Altherr MR , Schultz P , Olandt S , Frants RR , Pericak‐Vance M , Griggs RC . Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromosome 4q35 recombination events. Nat Genet 4: 165‐169, 1993.
 274. Wijmenga C , Brouwer OF , Moerer P , Padberg GW , Wijmenga C , Frants RR , Moerer P , Weber JL . Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet 336: 651‐653, 1990.
 275. Wijmenga C , Brouwer OF , Padberg GW , Frants RR . Transmission of de‐novo mutation associated with facioscapulohumeral muscular dystrophy. Lancet 340: 985‐986, 1992.
 276. Wijmenga C , Hewitt JE , Sandkuijl LA , Clark LN , Wright TJ , Dauwerse HG , Gruter A‐M , Hofker MH , Moerer P , Williamson R , van Ommen G‐JB , Padberg GW , Frants RR . Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 2: 26‐30, 1992.
 277. Wijmenga C , Padberg GW , Moerer P , Wiegant J , Liem L , Brouwer OF , Milner ECB , Weber JL , van Ommen GB , Sandkuyl LA , Frants RR . Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35‐qter by multipoint linkage analysis and in situ hybridization. Genomics 9: 570‐575, 1991.
 278. Wijmenga C , Sandkuijl LA , Moerer P , van der Boorn N , Bodrug SE , Ray PN , Brouwer OF , Murray JC , van Ommen GJB , Padberg GW , Frants RR . Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35‐qter. Am J Hum Genet 51: 411‐415, 1992.
 279. Wijmenga C , van Deutekom JCT , Hewitt JE , Padberg GW , van Ommen G‐JB , Hofker MH , Frants RR . Pulsed‐field gel electrophoresis of the D4F104S1 locus reveals the size and the parental origin of the facioscapulohumeral muscular dystrophy (FSHD)‐associated deletions. Genomics 19: 21‐26, 1994.
 280. Wijmenga C , Winokur S , Padberg G , Skraastad MI , Altherr MR , Wasmuth JJ , Murray JC , Hofker MH , Frants RR . The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus. Human Genetics 92: 198‐203, 1993.
 281. Wijmenga C , Wright TJ , Baan MJ , Padberg GW , Williamson R , van Ommen G‐JB , Hewitt J , Hofker MH , Frants RR . Physical mapping and YAC‐cloning connects four genetically distinct 4qter loci (D4S163, D4S139, D4F35S1 and D4F104S1) in the FSHD gene‐region. Hum Mol Genet 2: 1667‐1672, 1993.
 282. Winokur S , Bengtsson U , Feddersen J , Mathews K , Weiffenbach B , Bailey H , Markovich R , Murray J , Wasmuth J , Altherr MR , et al. The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin‐associated repetitive element: Implications for a role of chromatin structure in the pathogenesis of the disease. Chromosome Res 2: 225‐234, 1994.
 283. Winokur ST , Barrett K , Martin JH , Forrester JR , Simon M , Tawil R , Chung S‐A , Masny PS , Figlewicz DA . Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Neuromuscul Disord 13: 322‐333, 2003.
 284. Winokur ST , Bengtsson U , Vargas JC , Wasmuth JJ , Altherr MR . The evolutionary distribution and structural organization of the homeobox‐containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region. Hum Mol Genet 5: 1567‐1575, 1996.
 285. Winokur ST , Chen Y‐W , Masny PS , Martin JH , Ehmsen JT , Tapscott SJ , van der Maarel SM , Hayashi Y , Flanigan KM . Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet 12: 2895‐2907, 2003.
 286. Winston J , Duerden L , Mort M , Frayling IM , Rogers MT , Upadhyaya M . Identification of two novel SMCHD1 sequence variants in families with FSHD‐like muscular dystrophy. Eur J Hum Genet 23: 67‐71, 2015.
 287. Wright TJ , Wijmenga C , Clark LN , Frants RR , Williamson R , Hewitt JE . Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E‐11. Hum Mol Genet 2: 1673‐1678, 1993.
 288. Wright WG. Muscle training in the treatment of infantile paralysis. Boston Med Surg J 167: 567‐574, 1912.
 289. Wuebbles RD , Hanel ML , Jones PL . FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy‐associated vasculopathy. Dis Model Mech 2: 267‐274, 2009.
 290. Wuebbles RD , Long SW , Hanel ML , Jones PL . Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol 3: 386‐400, 2010.
 291. Xu H , Wang Z , Jin S , Hao H , Zheng L , Zhou B , Zhang W , Lv H , Yuan Y . Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression. Biochem Biophys Res Commun 446: 235‐240, 2014.
 292. Xu X , Tsumagari K , Sowden J , Tawil R , Boyle AP , Song L , Furey TS , Crawford GE , Ehrlich M . DNaseI hypersensitivity at gene‐poor, FSH dystrophy‐linked 4q35.2. Nucleic Acids Res 37: 7381‐7393, 2009.
 293. Xynos A , Neguembor MV , Caccia R , Licastro D , Nonis A , Di Serio C , Stupka E , Gabellini D . Overexpression of facioscapulohumeral muscular dystrophy region gene 1 causes primary defects in myogenic stem cells. J Cell Sci 126: 2236‐2245, 2013.
 294. Yang F , Shao C , Vedanarayanan V , Ehrlich M . Cytogenetic and immuno‐FISH analysis of the 4q subtelomeric region, which is associated with facioscapulohumeral muscular dystrophy. Chromosoma 112: 350‐359, 2004.
 295. Yao Z , Snider L , Balog J , Lemmers RJLF , Van Der Maarel SM , Tawil R , Tapscott SJ . DUX4‐induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet 23: 5342‐5352, 2014.
 296. Yip DJ , Picketts DJ . Increasing D4Z4 repeat copy number compromises #c2C12 myoblast differentiation. FEBS Lett 537: 133‐138, 2003.
 297. Young JM , Whiddon JL , Yao Z , Kasinathan B , Snider L , Geng LN , Balog J , Tawil R , van der Maarel SM , Tapscott SJ . DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet 9: e1003947, 2013.
 298. Zanou N , Gailly P . Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin‐like growth factors (IGFs) pathways. Cell Mol Life Sci 70: 4117‐4130, 2013.
 299. Zatz M , Marie SK , Cerqueira A , Vainzof M , Pavanello RC , Passos‐Bueno MR . The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet 77: 155‐161, 1998.
 300. Zeng W , Chen Y‐Y , Newkirk DA , Wu B , Balog J , Kong X , Ball AR , Zanotti S , Tawil R , Hashimoto N , Mortazavi A , van der Maarel SM , Yokomori K . Genetic and epigenetic characteristics of FSHD‐associated 4q and 10q D4Z4 that are distinct from non‐4q/10q D4Z4 homologs. Hum Mutat 35: 998‐1010, 2014.
 301. Zeng W , de Greef JC , Chen Y‐Y , Chien R , Kong X , Gregson HC , Winokur ST , Pyle A , Robertson KD , Schmiesing JA , Kimonis VE , Balog J , Frants RR , Ball AR, Jr. , Lock LF , Donovan PJ , van der Maarel SM , Yokomori K . Specific loss of histone H3 lysine 9 trimethylation and HP1?/Cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD). PLoS Genet 5: e1000559, 2009.
 302. Zhang Y , King OD , Rahimov F , Jones TI , Ward CW , Kerr JP , Liu N , Emerson CP , Kunkel LM , Partridge TA , Wagner KR . Human skeletal muscle xenograft as a new preclinical model for muscle disorders. Hum Mol Genet 23: 3180‐3188, 2014.
 303. Zhang Y , Lee JK , Toso EA , Lee JS , Choi SH , Slattery M , Aihara H , Kyba M . DNA‐binding sequence specificity of DUX4. Skeletal Muscle 6: 1‐11, 2016.

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).


Related Articles:

Exercise and Muscular Dystrophy: Implications and Analysis of Effects on Musculoskeletal and Cardiovascular Systems
Mechanisms of Muscle Injury, Repair, and Regeneration
Mechanisms Modulating Skeletal Muscle Phenotype
Regulation of Skeletal Muscle by microRNAs

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Facioscapulohumeral Muscular Dystrophy
 

How to Cite

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