Abstract
Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.
Highlights
The mutation causing the most common form of facioscapulohumeral muscular dystrophy (FSHD) was identified over 20 years ago, yet for many of the ensuing years there was little or no consensus in the scientific community regarding the molecular pathophysiology of the disease
Unlike other disease-causing mutations that disrupt the normal function of an identified gene, FSHD is caused by the loss of a subset of repeat units in the D4Z4 macrosatellite repeat array on chromosome 4 that does not disrupt the structure of any gene
Conclusions some areas of disagreement remain, there is increasing agreement and consensus on a model of FSHD pathophysiology that accounts for most of the current experimental findings. This model is based on the inefficient epigenetic repression of the DUX4 retrogene in the D4Z4 macrosattelite repeat adjacent to a polymorphic poly-adenylation sequence in the subtelomeric region of chromosome 4, and results in variegated expression of DUX4 in skeletal muscle nuclei in FSHD
Summary
The mutation causing the most common form of facioscapulohumeral muscular dystrophy (FSHD) was identified over 20 years ago, yet for many of the ensuing years there was little or no consensus in the scientific community regarding the molecular pathophysiology of the disease. Much more needs to be done to characterize these individuals, such as measuring the DUX4 protein and target genes, this observation suggests that other factors are necessary to initiate the disease process Determining whether these are modifier loci that protect the muscle cell in a cellautonomous or non-autonomous manner, for example, by preventing apoptosis or modulating an immune response, will greatly advance the understanding of FSHD pathophysiology. Taking advantage of the high frequency of somatic mosaicism for the D4Z4 repeat array contraction, isogenic clonal muscle cell lines were established from a muscle biopsy of a mosaic FSHD individual that only differ by the presence or absence of a D4Z4 repeat array contraction [107] These cell lines were useful to demonstrate that the burst-like feature of DUX4 expression is an intrinsic feature of the D4Z4 locus and, for the first time, showed that immortalized FSHD muscle cells can participate in muscle regeneration in vivo in immunodeficient host mice to overcome some of the limitations caused by the hominoid-specific features of DUX4. It will be important to further study the role of SMCHD1 and other epigenetic modifiers in relation to clinical variability of FSHD
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