Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

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Abstract

<p class="first" id="Par1">A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of <i>DUX4</i>, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. <i>DUX4</i> derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in <i>SMCHD1</i>, a gene involved in chromatin methylation (FSHD2). The resulting expression of <i>DUX4</i>, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting <i>DUX4</i> expression or blocking 1 or more of several downstream effects of <i>DUX4</i>. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed. </p><div class="section"> <a class="named-anchor" id="d936654e120">  </a> <h5 class="section-title" id="d936654e121">Electronic supplementary material</h5> <p id="d936654e123">The online version of this article (10.1007/s13311-018-00675-3) contains supplementary material, which is available to authorized users. </p> </div>

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A unifying genetic model for facioscapulohumeral muscular dystrophy.

Richard J. L. F. Lemmers, Patrick J. van der Vliet, Rinse Klooster … (2010)

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.

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Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2

Richard Lemmers, Rabi Tawil, Lisa Petek … (2012)

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by a contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here we show that mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

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A family of double-homeodomain transcription factors regulates zygotic genome activation in placental mammals

Alberto De Iaco, Evarist Planet, Andrea Coluccio … (2017)

In metazoan embryos, transcription is mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA) 1. Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio 2,3, but their mammalian homologues are still undefined. Here, we reveal that the DUX family of transcription factors 4 ,5 is essential to this process in human and mouse. First, human DUX4 and murine Dux are both expressed prior to ZGA in their respective species. Second, both orthologues bind the promoters and activate the transcription of ZGA genes. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents their cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA. We conclude that DUX proteins are key inducers of zygotic genome activation in placental mammals.