A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

Lemmers, Richard J.L.F.; Vliet, Patrick J. van der; Klooster, Rinse; Sacconi, Sabrina; Camaño, Pilar; Dauwerse, Johannes G.; Snider, Lauren; Straasheijm, Kirsten R.; Ommen, G J van; Padberg, George W.; Miller, Daniel G.; Tapscott, Stephen J.; Tawil, Rabi; Frants, Rune R.; Maarel, Silvère M. van der

doi:10.1126/science.1189044

Cited by 665 publications

(916 citation statements)

References 22 publications

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“…4 Recent work has suggested that both types of FSHD are characterized by expression and stabilization of mRNA produced from an open reading frame in the most telomeric D4Z4 repeat that encodes a potentially toxic protein: a long isoform of DUX4. 3,5,6 Weakness in FSHD appears to be of myogenic, rather than neurogenic, origin. 7 Many studies have, therefore, used primary myogenic cell cultures derived from FSHD subject biopsies to examine potential pathogenic mechanisms and therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of 499%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells.

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Section: Introductionmentioning

confidence: 99%

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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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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“…A number of 4q subtelomeric sequence variants are now recognised, although FSHD1 only occurs in association with 'permissive' haplotypes, each of which is associated with a polyadenylation signal located immediately distal of the last D4Z4 unit. 6,7 The resulting poly-A tail appears to stabilise DUX4 mRNAs transcribed from this most distal D4Z4 unit in FSHD muscle cells.…”

Section: Introductionmentioning

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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A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

Cited by 665 publications

References 22 publications

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

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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