BBADIS-63963; No. of pages: 8; 4C: 2 Biochimica et Biophysica Acta xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

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Review

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Facioscapulohumeral muscular dystrophy☆

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Sabrina Sacconi a,b,⁎, Leonardo Salviati c,d, Claude Desnuelle a,b

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Article history: Received 21 March 2014 Received in revised form 19 May 2014 Accepted 20 May 2014 Available online xxxx

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Keywords: Facioscapulohumeral muscular dystrophy Subtelomeric repeat DNA methylation SMCHD1 Epigenetics DUX4

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journal homepage: www.elsevier.com/locate/bbadis

Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151, route de Saint Antoine de Ginestière, 06202 Nice, France CNRS UMR7277, Inserm U1091, iBV — Institute of Biology Valrose, UNS Université Nice Sophia-Antipolis, Faculté de Médecine, 28 Avenue Valombrose, 06189 Nice Cedex, France c Clinical Genetics Unit, Dept. of Woman and Child Health, University of Padova, Italy d IRP Città della Speranza, Padova, Italy

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Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. © 2014 Published by Elsevier B.V.

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Facioscapulohumeral muscular dystrophy (FSHD) is the most common myopathy found in adults, with an overall incidence of more than 1:10,000 (source: Orphanet). It is classified among progressive muscular dystrophies, characterized by muscular fiber necrosis and degeneration giving rise to progressive muscular weakness and atrophy. A certain degree of T cell inflammation has been described in an FSHD patient's muscles and inflammation is thought to participate to the cascade of events inducing muscle degeneration [1,2]. FSHD is a genetically heterogeneous disorder and its genetic bases are unique and involve both genetic and epigenetic alterations. The vast majority of FSHD, indeed, are transmitted as an autosomal dominant trait with the disease locus mapping to the subtelomeric region of chromosome 4q. This form has been termed FSHD1. However some

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1. Introduction

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☆ This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. ⁎ Corresponding author at: Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151, route de Saint Antoine de Ginestière, 06202 Nice, France. Tel.: +33 492 035505; fax: +33 492 035891. E-mail addresses: [email protected], [email protected] (S. Sacconi).

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families, with an undistinguishable clinical phenotype display a more complex pattern of inheritance and a distinct genetic defect. This second form is termed FSHD2. In this review, we will discuss the clinical features, the molecular bases of FSHD, and the therapeutic strategies that are currently being tested.

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2. Clinical features

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FSHD was first described in the late 1800s by Louis Landouzy and Joseph Dejerine [3]. Their reports contain an accurate description of the key features of the disease, including early involvement of facial muscles, progressive weakness and atrophy of scapular and humeral muscles, and clinical variability among affected members of the same family. Disease onset is usually before the second decade; earlier onset is associated with more rapid progression and higher severity, indeed most of the FSHD patients who become wheelchair-bound have had a childhood onset of the disease [4]. These FSHD patients are also keener to develop extra muscular complication of the disease such as central nervous system (CNS) involvement [5–7], retinal telangiectasia [8] and hearing impairment.

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http://dx.doi.org/10.1016/j.bbadis.2014.05.021 0925-4439/© 2014 Published by Elsevier B.V.

Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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of FSHD showing mild involvement of the jaw and lingual muscles [23]. It is particularly frequent in early onset patients and in some cases required gastrostomy [7] Retinal telangiectasias may also be found in a limited number of FSHD patients; most of the time, they are asymptomatic. In rare cases, it may result in Coat's-like disease associated to abrupt retinal detachment with severe consequences up to irreversible blindness [19]. Except for one, all FSHD patients, who were reported in literature with a Coat's-like disease carry a contracted D4Z4 allele of less than 15 kb. Most of them are women [8]. CNS involvement is usually not described in FSHD patients, with the exception of some early onset cases who presented mental retardation and epilepsy [5–7]. However, studies evaluating subclinical CNS involvement in FSHD patients have shown an increased frequency of cerebral white matter lesions, motor cortex excitability abnormalities [24] and loss of gray matter in the left precentral cortex, and in the right fronto-polar and anterior cingulate regions [25]. FSHD2 patients do not seem to display a significantly different clinical phenotype compared to FSHD1, in terms of the pattern of muscular weakness and the frequency of extra muscular involvement except for retinal telangectasia that has never been described in these patients [26]. To date, no early onset FSHD2 patient has been reported in literature, besides a patient carrying both FSHD1 and FSHD2 who began to develop symptoms in early childhood [12]. Studies are ongoing in FSHD2 patients, to establish the clinical effects of hypomethylation found on other regions of the genome [27] and which may also be present in the relatives without the 4qA allele and consequently not displaying muscular features of FSHD.

In most patients, FSHD is inherited as an autosomal dominant trait (FSHD1) and de novo cases accounting for around 25% [28,29] of patients. Often de novo cases are in the mosaic form. Linkage studies on large families have mapped the disease locus to the subtelomeric region of chromosome 4, more specifically at 4q35-qter [30–32]. This chromosomal region lacked classical genes but contains a macrosatellite repeat comprised of an array of repeated 3.3 kb units, called D4Z4. Analysis of a large population of healthy subjects and FSHD patients established in the past that the number of D4Z4 repeated units on chromosome 4 varies in the general population between 11 and 110, whereas FSHD patients carry a contracted allele from 1 to 10 repeated units [29,33]. There is a rough correlation between D4Z4 repeat number, age of onset and severity of clinical phenotype. Patients carrying the lower number of repeats are the most severely affected [34], while those

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Penetrance was initially thought to be complete before age 20 [9], however some obligate carriers remain asymptomatic throughout their lives [10–12]. Larger studies are needed to clarify the actual penetrance of the disease. A marked intra- and interfamilial variability is remarkable in the clinical presentation; usually females display later onset and a slower progression. Moreover a higher proportion of asymptomatic carriers are females [13]. Interestingly, in women expressing the disease, the severity becomes more important after menopause and no difference between male and female populations has been reported in a genotype/phenotype correlation study of elder patients (Sacconi, unpublished results). These findings suggest a possible protective role of estrogen that has to be investigated in further studies. The main characteristics of muscular involvement in FSHD are asymmetry, selectivity, and the progression profile. Asymmetric involvement, which is rarely encountered in other limb girdle muscular dystrophies, is almost always present in FSHD patients and it is not related to handedness [14]. Muscular weakness usually spreads from the face to the limbs, but progression is extremely variable. Selectivity of muscular involvement is another peculiar characteristic of FSHD (Fig. 1). One third of patients will display only facial and shoulder muscle weakness; in the remaining patients, weakness will spread to anterior arm muscles, abdominal muscles and/or pelvic girdle muscles. Respiratory muscle weakness is not very frequent and is usually secondary to thoracic deformations [15]. Restrictive respiratory muscle involvement seems more frequent in FSHD2 [16]. However, the high prevalence of sleep-disordered breathing was noted in patients with FSHD, independently to the severity of muscular involvement requiring, in a minority of cases, positive airway pressure [17]. Weakness usually progresses very slowly, allowing FSHD patients to adapt and compensate muscular deficiencies, at least at the functional level. In some patients, course is characterized by relapses followed by long intervals of stable clinical conditions. The majority of patients will retain the ability to walk, although many experience severe limitations in everyday life activities. 10–20% of FSHD patients are wheelchairbound [9,18]. Life expectancy is not significantly reduced, except for early onset patients with the more severe forms, or when correct care is not instituted. Although FSHD is considered as a skeletal muscle specific disease, extra muscular involvement has been reported. Sensorineural hearing loss seems to be quite frequent, since in various studies, it has been reported in 25 to 65% of patients [8,18,20,21] even though most of the patients present with subclinical impairment; severe hearing loss is more frequent in early onset patients [7]. Cardiomyopathy is rare [9], however, some patients may present with heart conduction defects [22]. Dysphagia has been described in patients with advanced stages

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Fig. 1. Selectivity of muscular involvement in FSHD patient. Different levels of muscular dystrophy can be found in different muscles of an FSHD patient. A) Deltoid; mild myopathic changes, increased percentage of internalized nuclei, increased fiber type variability with some (partially) atrophic muscle fibers. B) Biceps: moderate myopathic changes. C) Trapezius: advanced dystrophic changes.

Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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Monosomy 4q is not associated with the appearance of a clinical phenotype and at least one D4Z4 repeat from chromosome 4 is necessary to develop FSHD [51]. This finding brought the attention on the structure of the D4Z4 repeats on chromosome 4. Every D4Z4 repeat contains an open reading frame (ORF) coding for DUX4 [52–56], a retrogene which ancestrally originated from the retrotransposition of the mRNA of DUX4c. DUX4c is still present in the majority of mammals [57] but has been lost in the primate lineage. DUX4 encodes for a putative transcription factor that contains two homeobox domains. It is normally expressed in human testis and during early development, but it is repressed during cellular differentiation. DUX4 expression in muscle cells induces the expression of germline genes and immune mediators, but also of retrotransposons, endogenous retrovirus elements, and pericentromeric satellite HSATII sequences [58,59]. Some of these elements may create alternative promoters for genes causing production of non-physiological transcripts, long noncoding RNAs, or antisense transcripts. All these factors are likely to be involved in the downstream cascade of intracellular and extracellular events leading to muscle degeneration. Since DUX4 expression is transient and is limited to a specific time window, these transcripts could also be used as biomarkers of the disease. Therefore FSHD is associated with the failure to maintain complete suppression of DUX4 expression in differentiated skeletal muscle (and other tissues). Overexpression of DUX4 in a zebrafish model recapitulates the features of FSHD thus confirming the relationship between DUX4 and FSHD and underlining the importance of DUX4 expression in FSHD pathophysiology during development [60]. More recently transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele have been generated recapitulating several genetic and epigenetic features seen in FSHD patients: high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation [61]. The exact relationship between D4Z4 repeat contraction on chromosome 4 and overexpression of DUX4 was clarified only recently. A detailed analysis of the 4q subtelomeric region revealed that only the most telomeric D4Z4 repeat can produce DUX4 transcripts. In fact D4Z4 contains only exons 1 and 2 of DUX4, while the rest of the gene is located on the non-repetitive region distal to the last D4Z4 repeat. This region includes also a sequence termed pLAM that contains a polyadenylation consensus sequence that is necessary for the proper maturation of DUX4 transcripts. This consensus is functional only in the permissive 4qA chromosomes but not in 4qB or 10q chromosomes. Therefore only DUX4 transcripts originating from the last repeat on the 4qA chromosome can be polyadenylated and are stable (and can be translated into protein) while those expressed from 4qB or 10q chromosomes are rapidly degraded [62] (Fig. 2). The size of the 4q telomere could also be important in modulating DUX4 expression, especially in the presence of a contracted D4Z4 repeat. Shortening of the telomeric repeats with each cell division could explain disease progression. Using a cell culture model, Stadler et al. [63]

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The interpretation of the results obtained in the remaining 6 healthy subjects carrying 4–6 repeated units on permissive 4qA chromosomes is more complicated. The lack of precise clinical data and the fact that nonpathogenic chromosome 4 and 10 rearrangements could have been missed by the testing protocol may explain these results, but further genetic and clinical studies are warranted to clarify this issue. In the same article, 3 over 223 unrelated FSHD patients were found to carry a 4qB allele in association with the FSHD phenotype. We have demonstrated previously that several diseases can mimic very closely FSHD in the presence of a 4qB-contracted allele and must be excluded before concluding for FSHD diagnosis [49,50].

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with 9 or 10 repeats may be paucisymptomatic or asymptomatic, besides a few exceptions. FSHD1 was therefore defined as a “repeat contraction” disorder. It should be noted that unlike repeat expansion disorders, FSHD1 does not display the phenomenon of anticipation, and the size of the contracted D4Z4 arrays is stable within families. The clinical diagnosis of FSHD is confirmed by molecular analysis, bypassing the need for muscle biopsy in most cases. Standard molecular testing for FSHD1 demonstrates the presence of a contraction of the D4Z4 repeated units in one copy of 4q35. The molecular diagnosis of FSHD1 is performed by a classical technique, consisting of a Southern blot [29,33] using the p13E-11 probe, on linear gel electrophoresis (LGE), which recognizes a region proximal to the D4Z4 locus on chromosome 4, after a double digestion of the DNA with EcoRI and BlnI enzymes. Normal individuals usually harbor fragments larger than 38 kb. The high homology between chromosomes 10q and 4q (98% of the sequence is identical) is the basis for the relatively frequent genomic rearrangements affecting this region. D4Z4 repeats with a typical 10q sequence have been observed on 4q chromosomes in 10% of the Dutch population. The reverse configuration is also quite frequent [35, 36], demonstrating that homologous domains 4q and 10q are highly dynamic and that FSHD is not due to an alteration of a specific molecular composition of D4Z4 elements but to their structural organization on the 4q35 region [37,38]. Rearrangements between 4q and 10q chromosomes may complicate the diagnosis of FSHD1, generating false negative or false positive results and must be researched in all cases when clinical data do not correspond to genetic results. A recent study on single-nucleotide polymorphisms localized on the D4Z4 locus allowed the identification of nine different haplotypes [39] in the general population. Only a few of them, all 4qA types, are associated with the disease. The most frequent among these “permissive” haplotypes is 4A161 [40,41]. In a reduced percentage of cases, around 5%, D4Z4 allele contraction on chromosome 4 may not be detected with the standard analysis because of the presence of a proximal deletion of D4Z4 repeated units including the p13E-11 region [44,45]. The high incidence of somatic mosaicism in de novo patients may be also a source of diagnostic errors because they are under recognized by classical LGE. These patients are sporadic cases and show usually mild phenotypes or atypical clinical pictures [46]. The use of pulse field gel electrophoresis (PFGE) is highly recommended, as well as 4qA and 4qB determination. In dubious cases, it is important to search for rearrangements between chromosomes 10 and 4 and proximal deletions including the p13E-11 probe region by using specific protocols, including additional restriction enzyme digestion combined or not with additional probes. These approaches are however technically challenging and there are efforts aimed at simplifying the task. One of these is molecular combing, an approach based on fluorescent in situ hybridization, which has shown promising results, but it has not yet entered clinical practice [47]. Another proposed method employs genotyping of a set of SNP in this region and allows avoiding Southern blot studies in selected cases and could be useful for prenatal or preimplantation genetic diagnosis [48]. In a recent large-scale population study the current criteria for FSHD1 molecular analysis were challenged, in particular concerning the penetrance of this disease and its association with the 4qA allelic variant. Indeed, among the 801 healthy subjects analyzed in this study, 16 (2.1%) were found to carry a 4qA contracted D4Z4 allele on chromosome 4qA of less than 11 repeats. In 10 of these healthy subjects, the incomplete of penetrance of borderline alleles comprised between 7 and 10 repeats may explain the lack of clinical manifestations. In fact, borderline alleles may be more frequent than currently thought in the general population and could result in a clinical phenotype only in the presence of genetic, epigenetic, or environmental modifiers.

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Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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Fig. 2. Structure of the 4q subtelomeric region. A) Comprehensive view of the 4q subtelomeric region with the D4Z4 macrosatellite repeat. The p13E-11 is the probe commonly employed for Southern blot analysis of patients. 4qA and 4qB are allelic. B) Arrangement of DUX4 in D4Z4 repeats. Each unit contains sequences corresponding to DUX4 exons 1 and 2. Exon 3 is located outside of the repeated region, therefore only the last unit can be expressed (if located on a permissive chromosome). C) Structure of the DUX4 gene and of its two transcripts found in muscle.

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demonstrated that telomere shortening is associated with a progressive upregulation of DUX4-fl expression in cells from FSHD subjects. Overexpression is inversely proportional to telomere length and this effect is observed long before terminal telomere shortening would induce replicative senescence. To make matters even more complicated, besides the full length DUX4 transcript (DUX4-fl) a shorter form exists (DUX4-s) that lacks a part of exon 1 because of a non-canonical alternative splice consensus within the DUX4 ORF [64]. DUX4-s lacks the C-terminal of DUX4-fl and does not elicit apoptosis when expressed. Its physiological function is still unclear. DUX4-fl is produced from the last D4Z4 unit in early stem cells, while in differentiated tissues, the D4Z4 array is normally associated with histone H3 with a trimethylated lysine at position 9 which represses DUX4 expression [65]. The transcripts that escape repression, are preferentially spliced using the alternative splicing consensus, producing DUX4-s instead of DUX4-fl. Contraction of the D4Z4 arrays inhibits the conversion to repressive chromatin, and DUX4 is transcribed, and is spliced using the canonical exon 1 consensus, thereby forming DUX4-fl. The specific de-repression of DUX4 transcription in skeletal muscle and not, or only marginally, in other adult tissues in FSHD is explained by the presence upstream of the D4Z4 array of two muscle specific enhancer sequences (DME1 and DME2) which interact with the DUX4

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promoter in vivo and are able to activate DUX4-fl expression in myocytes but not in other cell types [66]. Therefore, several events concur to determine FSHD1: 1) there must be a contraction of the D4Z4 repeat array on 4q35; 2) the contraction is associated with chromatin relaxation and hypomethylation of the region; 3) DUX4 is transcribed; and 4) the transcript must be polyadenylated and this can occur only when contractions affect 4qA type chromosomes. In the testis (and only in the testis) other polyadenylation sites, distal to the pLAM region, are activated, thereby allowing the expression of DUX4 also from 4qB chromosomes [64]. This model accounts also for the observation that deletions of the entire D4Z4 array are not associated with FSHD and excludes a major role in the pathogenesis of the disease of transcriptional deregulation of neighboring genes [51].

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A small proportion of patients (around 5–10%) with features of FSHD do not harbor a contraction of the 4q35 D4Z4 array and they often have a complex pattern of inheritance. The molecular basis of this second form of FSHD, termed FSHD2, has remained obscure for many years. Since FSHD1 patients have been shown to display hypomethylation restricted to the D4Z4 contracted allele on chromosome 4 [67] patients presenting with an FSHD phenotype carrying a normal sized D4Z4 allele

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Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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We have recently identified a number of patients harboring 9 D4Z4 repeated units on 4qA chromosomes who presented with very severe clinical phenotypes compared to the number of residual repeats. These patients had profound hypomethylation on chromosome 4qA and were found to harbor SMCHD1 mutations. Detailed analysis of the families revealed, as expected, that the two defects may segregate independently in the pedigrees and that patients affected by either defect alone presented with a mild form of FSHD1 or FSHD2 (in this case only if another 4qA allele was present), while a severe phenotype was observed if both defects were transmitted to the offspring. The D4Z4 contraction and SMCHD1 mutations have an additive effect on D4Z4 methylation resulting in a further increase of DUX4-fl overexpression, and thus a more severe phenotype. In this view, the SMCHD1 mutations are a modulator of the severity of the D4Z4 contraction. But the opposite is also true: the D4Z4 contraction modulates the severity of the phenotype associated with SMCHD1 mutations.

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polymorphism) in order for the DUX4 transcripts to be polyadenylated and translated into protein. Finally, although there are known phenocopies of FSHD, which may be associated to mutations in other genes (CAPN3, VCP) [46], there are still patients with an FSHD-like phenotype who lack a clear molecular defect. Some of them show an extended hypomethylation but no SMCHD1 mutation. Although for some patients, technical issues may limit the detection of mutation in the SMCHD1 gene, another interesting possibility is that mutations in other genes involved in chromatin maintenance may account for these cases.

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on chromosome 4 were analyzed for methylation. Most of these patients, called FSHD2, were found to harbor at least one chromosome 4qA and displayed a marked hypomethylation of chromosome 4 suggesting a common pathophysiological pathway in both conditions [68]. Chromatin studies in FSHD2 patients showed the presence of D4Z4 chromatin relaxation leading to DUX4-fl expression [43]. Interesting hypomethylation was found also on chromosome 10q (which is normally methylated in FSHD1 patients) and in other regions of the genome [27]. In FSHD2 families, 4q hypomethylation segregated independently from the disease; only patients who had 4q hypomethylation and at least one 4qA allele developed FSHD while those with 2 4qB type alleles were healthy. This was consistent with a genetic defect impairing chromatin condensation and methylation independent from the D4Z4 arrays, affecting also other genomic targets. This defect was identified in 2012 thanks to a next generation sequencing approach. FSHD2 patients were shown to harbor heterozygous mutations in SMCHD1 on chromosome 18p11.32, a gene essential for the inactivation of the X chromosome. Mutations apparently cause a loss of function of the protein and the pathogenesis of the disease is likely due to SMCHD1 haploinsufficiency. Therefore FSHD2 is a digenic disorder, which requires both a mutation inactivating one copy of SMCHD1 and a permissive 4qA allele (Fig. 3). In conclusion, both FSHD1 and FSHD2 result from the inappropriate expression of DUX4 in differentiated tissues. In FSHD1, this occurs because the contracted D4Z4 repeats cannot form repressive heterochromatine, and in FSHD2 because one of the effector genes required for methylation (and repression of DUX4) is haploinsufficient. In both situations, the defect must be associated with a 4qA allele (in the case of FSHD1, the contraction must be in cis with the 4qA

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Fig. 3. Genetic and epigenetic mechanisms of FSHD1, FSHD2, and FSHD1 + 2. A) In normal individuals the 4q35 region comprises an array containing 11–100 D4Z4 repeats. It is highly methylated and has a heterochromatic structure. DUX4 transcription may take place but transcripts are rapidly degraded. B) In FSHD1 patients, pathogenic contraction of the D4Z4 array (1–10 repeats) on a permissive chromosome causes hypomethylation and chromatin relaxation of this region. DUX4 is transcribed and transcripts are stabilized by polyadenylation. Polyadenylation signal (PAS) is located distally to the D4Z4 last repeat. C) FSHD2 patients harbor a normal sized D4Z4 repeat allele on a permissive chromosome 4 but a mutation of the SMCHD1 gene on chromosome 18. Haploinsufficiency of SMCHD1 causes marked hypomethylation and chromatin relaxation on 4q35, thus increasing DUX4 transcription. Only transcripts from permissive 4q alleles can be stabilized by polyadenylation. D) FSHD1 + 2 patients, present with a pathogenic D4Z4 contracted allele on 4q35 (b11 repeats) in a permissive chromosome and a SMCHD1 mutation, with an additive effect on D4Z4 hypomethylation and chromatine relaxation and an overexpression of DUX4 transcripts.

Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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No etiological therapy is available, to date, for FSHD patients, mainly due to the fact that the physiopathological mechanism of FSHD is still not completely clear. Nevertheless, a number of pharmacological strategies have been tested in order to slow down or stop disease progression. Since, around 40% of FSHD muscle biopsies show T cell inflammatory infiltrate, corticosteroids were tried in a number of cases without any result [69–71]. Several studies were conducted on β2 agonists because they have an anabolic effect [72,73] but long-term studies did not provide any evidence for their effectiveness. An open study was conducted on FSHD1 patients to analyze the effects of methionine and folic acid, which are supposed to increase methylation. Neither clinical effect nor DNA methylation increases in peripheral blood lymphocytes were observed after 12 weeks of treatment [74]. Myostatin negatively controls satellite cell proliferation and differentiation [75]. In 2005, Wyeth laboratories started a controlled double-blind trial for patients suffering from various types of muscular dystrophies, including FSHD1, testing an antibody (MYO-029) against myostatin. After 54 weeks of treatment, the trial was stopped because, even though no sign of toxicity was reported, no effect was evident in any of these patients [76]. In vitro studies have shown that oxidative stress plays an important role in determining DUX4 toxicity, therefore stimulating the oxidative stress response pathway could be beneficial in FSHD [77], but no patient data are available at the moment. Transplantation of cultured myoblasts by intramuscular injection has been considered for a number of dystrophies and, in particular, in Duchenne Muscular Dystrophy (DMD). Because FSHD is characterized by selective muscle involvement, FSHD patients display a wide spectrum of affected and unaffected muscles. We have demonstrated [78] that myoblast cell cultures derived from histologically unaffected FSHD muscles were normal in all aspects of cell proliferation and in vitro and in vivo differentiation. We suggested that such myoblasts could be used for autologous cell therapy in FSHD, eliminating the need of immunosuppression and a therapeutic trial, exploring the feasibility and efficacy of this approach is still ongoing in our Institution. Meanwhile, another type of myogenic mesodermal stem cell, mesangioblast, has been considered in view of future autologous therapeutic trials. Mesangioblasts were shown to improve muscle morphology and function when injected intra-arterially in animal models of dystrophy. Since they can be delivered through the circulation to whole body muscles, mesangioblasts could represent a more effective alternative for autologous cell therapy in comparison to myoblasts that have to be injected locally. Moreover, mesangioblasts derived from pathologically affected FSHD muscle were morphologically abnormal and had a block in differentiation, while mesangioblasts derived from morphologically normal FSHD muscle did not show such abnormalities [79]. However, recent studies analyzing the level of DUX4-fl expression in affected and non-affected muscles and/or myogenic derived cells showed no significant difference in the expression of this transcript related to the level of muscular dystrophy (Sacconi, unpublished results). Environmental or structural factors may also contribute to different tissue sensitivities to DUX4-fl expression and, consequently, they may considerably limit the effect of autologous cell therapy. Several groups are working on developing gene therapy for FSHD1 patients. Most of them are focused in suppressing DUX4 gene expression by using siRNA or RNA-like antisense oligonucleotides (AONs), as it has been done in DMD. The goal is to interfere with DUX4 mRNA processing

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and stability, or alter the splicing of the DUX4 transcript to reduce the amount of DUX4-fl in favor of DUX4-s. In the absence of an effective etiological therapy, the correct management of symptoms and of secondary involvement is essential to slow down disease progression in order to conserve as long as possible functional autonomy and adequate quality of life. It is also important to identify precociously retinal and auditory complications, to treat scoliosis and to monitor respiratory insufficiency (especially in severe forms). It is possible to perform surgery for winged scapula, although this technique is still controversial. The role of exercise in maintaining or improving muscular force and/ or functional ability is still controversial, because of the lack of controlled studies and because vigorous exercise could theoretically worsen muscular weakness inducing rhabdomyolysis. However there are no indications that FSHD muscle fibers are more likely to mechanical injury as are dystrophies with sarcolemmal abnormalities. In fact, several studies have shown that both strength training and aerobic exercise in FSHD have at least a short-term beneficial effect [80]. These observations were confirmed in a prospective 1-year trial [81]. In a recent, uncontrolled before–after trial, we demonstrate the feasibility, safety, and effectiveness of neuromuscular electrical stimulation strength training in FSHD1 patients [82]. Physical therapy should promote a non-sedentary life style, joint flexibility training to avoid retractions and improve muscle strength and aerobic capacity by mild aerobic exercising. Future randomized controlled studies are necessary to better define and broaden these recommendations.

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Over the last decade, there were major advances in the understanding of the genetic and epigenetic bases of FSHD and its pathophysiology. Nevertheless there are important issues that are still a matter of investigation. Even though genetic and epigenetic evidence is strongly in favor of a major role of DUX4, the exact pathophysiological mechanism remains to be defined. This knowledge is crucial to develop novel pharmacological approaches. The bases of the selectivity of muscle involvement are also largely obscure as well as of the milder phenotypes observed in females. Variability of clinical phenotype is explained only in part by the extent of D4Z4 contraction. The possibility that modifier genes other than SMCHD1 may contribute in worsening or improving clinical expression of the disease is tempting and need to be further investigated. These genes may be involved in epigenetic regulation of the D4Z4 region and may be responsible for other forms of FSHD in a minority of patients who lack genetic diagnosis. Understanding all these issues may contribute in developing novel therapeutic approaches for FSHD.

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Further studies are ongoing to ascertain whether SMCHD1 mutations or borderline D4Z4 contractions could act as genetic modifiers for other diseases.

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We kindly thank Miss Pauline Lahaut for her help in collecting data for the article. S. Sacconi and C. Desnuelle are supported by AFM-Telethon, French Association against Myopathy. S.S. is also supported by a grant from ANR, French National Agency for Research (Grant ANR-13-BSV1-000404). L. Salviati is supported by a grant from Fondazione CARIPARO (Padova, Italy). The authors do not disclose actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work.

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Please cite this article as: S. Sacconi, et al., Facioscapulohumeral muscular dystrophy, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbadis.2014.05.021

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