Specific Sequence Variations within the 4q35 Region Are Associated with Facioscapulohumeral Muscular Dystrophy

Lemmers, Richard J.L.F.; Wohlgemuth, M.; Gaag, Kristiaan J. van der; Vliet, Patrick J. van der; Teijlingen, Corrie M.M. van; Knijff, Peter de; Padberg, George W.; Frants, Rune R.; Maarel, Silvère M. van der

doi:10.1086/521986

Cited by 198 publications

(246 citation statements)

References 22 publications

(46 reference statements)

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“…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] . With the initial identification of two allelic variants of the 4q subtelomere, 4qA and 4qB [16] and the recent further specification into 9 different haplotypes of chromosome 4q [17] , it has become evident that D4Z4 contraction alone is not sufficient to cause FSHD. Instead, it needs to occur on a specific genetic background, the 4qA161 haplotype.…”

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…Of note, the same haplotypes are also found in the duplicated FR-MAR present within the q26 region of human chromosome 10. [22][23][24] Consequently, any cell contains four copies and up to four haplotypes of the FR-MAR. All four copies of FR-MAR are attached to the NM in normal primary human myoblasts, as was previously demonstrated by in situ fluorescent hybridization on nuclear halos.…”

Section: Resultsmentioning

confidence: 99%

“…These 8nt þ haplotypes are generally not associated with the FSHD phenotype. [22][23][24] Next, we have analyzed the level of DNA methylation at four CpGs in the FR-MAR region in relation with NM attachment. One of the four CpGs, CpG 4 , was found to be 100% methylated in the NM fraction.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several SSLPs have been identified that are specifically associated with FSHD. [22][23][24] Finally, the chromatin structure and DNA methylation level could also modify the FR-MAR binding to the NM. Other genetic and epigenetic abnormalities affecting the subtelomeric region of chromosome 4q have also been observed in various pathologies including the Rett and ICF syndromes, 25 as well as in several types of cancer.…”

Section: Introductionmentioning

confidence: 99%

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DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

et al. 2014

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Mechanisms that regulate attachment of the scaffold/matrix attachment regions (S/MARs) to the nuclear matrix remain largely unknown. We have studied the effect of simple sequence length polymorphism (SSLP), DNA methylation and chromatin organization in an S/MAR implicated in facioscapulohumeral dystrophy (FSHD), a hereditary disease linked to a partial deletion of the D4Z4 repeat array on chromosome 4q. This FSHD-related nuclear matrix attachment region (FR-MAR) loses its efficiency in myoblasts from FSHD patients. Three criteria were found to be important for high-affinity interaction between the FR-MAR and the nuclear matrix: the presence of a specific SSLP haplotype in chromosomal DNA, the methylation of one specific CpG within the FR-MAR and the absence of histone H3 acetylated on lysine 9 in the relevant chromatin fragment.

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“…13,14 4q35.2-associated haplotypes were assessed as previously reported. 15,16 D4Z4 methylation analysis Methylation-sensitive restriction digestion. The methylation level in the 4q-associated proximal D4Z4 tandem repeat was determined using the methylation-sensitive enzyme Fse1.…”

Section: Methodsmentioning

confidence: 99%

Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Winston¹,

Duerden²,

Mort³

et al. 2014

Eur J Hum Genet

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Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had 411 D4Z4 repeats. SMCHD1 c.1040 þ 1G4A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G4T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD.

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Specific Sequence Variations within the 4q35 Region Are Associated with Facioscapulohumeral Muscular Dystrophy

Cited by 198 publications

References 22 publications

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

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

DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

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