Physical Mapping Evidence for a Duplicated Region on Chromosome 10qter Showing High Homology with the Facioscapulohumeral Muscular Dystrophy Locus on Chromosome 4qter

Deidda, G.; Cacurri, S.; Grisanti, Paola; Vigneti, Eliana; Piazzo, N.; Felicetti, L.

doi:10.1159/000472291

Cited by 89 publications

(64 citation statements)

References 9 publications

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“…Not surprisingly, these large deletions of subtelomeric macrosatellite DNA in FSHD1 correlate with epigenetic changes at 4q35, discussed next, which appear to be essential for developing disease (40,160). It is interesting to note that chromosome 10q26 contains a subtelomeric D4Z4 macrosatellite that is highly homologous to the array at 4q35 (5,41); however, FSHD1 is linked only to contractions on chromosome 4 and D4Z4 contractions at 10q26 are non-pathogenic (99,100,130,181). Thus, in combination with the clinical diagnosis, the genetic diagnosis for FSHD1 is a contraction at 4q35 to 1-11 D4Z4 repeats, in cis with a permissive 4qA subtelomere.…”

Section: Fshd Genetics and Clinical Presentationmentioning

confidence: 95%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

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Section: Fshd Genetics and Clinical Presentationmentioning

confidence: 95%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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“…The 3.3-kb repeat unit was named D4Z4, and variable copy numbers are repeated in tandem in a head-to-tail orientation at the 4q35 locus. A number of D4Z4-like sequences are found throughout the human genome, most of which are associated with acrocentric chromosomes, however, only the D4Z4 repeat array situated at 10q26 exhibits almost complete sequence identity (*99%) to the 4q35 array (Lyle et al 1995;Winokur et al 1996;Beckers et al 2001;Deidda et al 1995). Each 3.3-kb repeat unit has a complex sequence structure, with several GC-rich repeat sequences and an open reading frame containing two homeobox sequences designated as DUX4 (double homeobox 4) (Hewitt et al 1994;Gabriëls et al 1999;Ding et al 1998) (Fig.…”

Section: Genetics Of Fshdmentioning

confidence: 99%

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

et al. 2011

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

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“…Sequences homologous to D4Z4 have been identified on many, mainly acrocentric, chromosomes [10] . Due to an ancient duplication event, the subtelomere of chromosome 10q also contains a D4Z4-like repeat [11,12] and in ~20% of individuals subtelomeric exchanges between repeats on 4q and 10q can be observed [13] . However, repeat contractions on 10q do not cause FSHD, although ~25% of chromosomes 10q carry a repeat array of 10 units or less [14,15] .…”

Section: Introductionmentioning

confidence: 99%

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

et al. 2009

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Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date however, the methylation status of contracted repeats on non-pathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a non-pathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In fifteen FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD; (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.

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Physical Mapping Evidence for a Duplicated Region on Chromosome 10qter Showing High Homology with the Facioscapulohumeral Muscular Dystrophy Locus on Chromosome 4qter

Cited by 89 publications

References 9 publications

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

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