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Review
. 2012 Oct;25(5):614-20.
doi: 10.1097/WCO.0b013e328357f22d.

Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

Silvère M van der Maarel  1 , Daniel G Miller, Rabi Tawil, Galina N Filippova, Stephen J Tapscott
Affiliations
Review

Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

Silvère M van der Maarel et al. Curr Opin Neurol. 2012 Oct.

Abstract

Purpose of review: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder.

Recent findings: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements.

Summary: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies.

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Figures

Figure 1
Figure 1
(Epi)genetic mechanism of FSHD1 and FSHD2. A) Normally the D4Z4 repeat (triangles) on DUX4 polyadenylation site containing (PAS) and non-containing genetic backgrounds varies between 11-100 units and contains heterochromatic modifications (black circles). By D4Z4 contraction to 1-10 units in FSHD1, or by an unknown mechanism in FSHD2, the chromatin structure of the D4Z4 repeat becomes relaxed (light grey circles) leading to the production of DUX4 mRNA and protein (G-TF: germline transcription factor). Alleles that do not contain a PAS also show chromatin relaxation but fail to produce stable DUX4 mRNA and protein. B) FSHD permissive alleles contain an extra exon for DUX4 immediately distal to the D4Z4 repeat array that provides this retrogene with a PAS. Non-permissive fail to stabilize DUX4 mRNA in the absence of this exon/PAS signal. C) In myotube cultures of FSHD1 and FSHD2 patients, a variegated pattern of DUX4 immunoreactive nuclei (black nuclei) can be observed.
See this image and copyright information in PMC

References

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