Clinical features of facioscapulohumeral muscular dystrophy 2

Greef, Jessica C. de; Lemmers, Richard J.L.F.; Camaño, Pilar; Day, John W.; Sacconi, Sabrina; Dunand, Murielle; Engelen, B.G.M. van; Kiuru-Enari, Sari; Padberg, G.W.A.M.; Rosa, Alberto L.; Desnuelle, Claude; Spuler, Simone; Tarnopolsky, Mark A.; Venance, Shannon L.; Frants, Rune R.; Maarel, Silvère M. van der; Tawil, Rabi

doi:10.1212/wnl.0b013e3181f96175

Cited by 159 publications

(154 citation statements)

References 23 publications

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“…2,3 A small percentage of FSHD subjects (FSHD2) show the FSHD muscle weakness pattern but do not have a contracted 4q D4Z4 array. 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.…”

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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“…With regards to the mother (385-102), the size of her permissive allele (27 units) might explain why she is not affected with FSHD, despite her SMCHD1 variant and D4Z4 hypomethylation. In 2010, de Greef et al 4 showed that the average size of the shortest permissive allele in FSHD2 is 16 units, which is much shorter than the average of 28 units found in control individuals, which was confirmed in a later study. 4,21 The permissive allele in the proband (385-203) and his mother (385-102) is 27 units, relatively long for FSHD2.…”

Section: A a T T A A A G T A A G T A T C T A A T T A A A G T A A G T mentioning

confidence: 74%

“…3 The genetic forms identified thus far, FSHD1 and FSHD2, are clinically indistinguishable. 4 Both forms are associated with partial chromatin relaxation of the D4Z4 macrosatellite repeat array on the subtelomere of the long arm of chromosome 4 and transcriptional derepression of the D4Z4 unit-encoded DUX4 retrogene in skeletal muscle. [5][6][7][8][9] DUX4 is a germ line transcription factor that is normally repressed in somatic cells.…”

Section: Introductionmentioning

confidence: 99%

“…5 In FSHD1, chromatin relaxation and CpG hypomethylation are restricted to the contracted allele, whereas in FSHD2 chromatin relaxation and CpG hypomethylation occur at the D4Z4 repeat arrays of both copies of chromosome 4 and in the highly homologous repeat arrays on chromosome 10. 4,9 Heterozygous variants in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene on chromosome 18 account for the majority of FSHD2 cases. 14 SMCHD1 is an atypical member of the SMC gene superfamily, a family of proteins which is involved in chromosome condensation and cohesion, genome maintenance and gene regulation.…”

Section: Introductionmentioning

confidence: 99%

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Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

et al. 2015

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Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 functionaffecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

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“…24 Although FSHD1 and FSHD2 have different underlying genetic defects, they both appear to be caused by transcriptional derepression of DUX4 in skeletal muscle. 11 The contraction of D4Z4 repeats in FSHD1 is associated with partial demethylation of the shortened allele, and relaxation of the local chromatin structure, whereas, in FSHD2, global genomic demethylation is observed.…”

Section: Discussionmentioning

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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Clinical features of facioscapulohumeral muscular dystrophy 2

Abstract: Clinically, patients with FSHD2 are indistinguishable from patients with FSHD1. The present data suggest that FSHD1 and FSHD2 are the result of the same pathophysiologic process.

Cited by 159 publications

References 23 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

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

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

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