Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle dystrophy typically affecting patients within their second decade. Patients initially exhibit asymmetric facial and humeral muscle damage, followed by lower body muscle involvement. FSHD is associated with a derepression of DUX4 gene encoded by the D4Z4 macrosatellite located on the subtelomeric part of chromosome 4. DUX4 is a highly regulated transcription factor and its expression in skeletal muscle contributes to multiple cellular toxicities and pathologies ultimately leading to muscle weakness and atrophy. Since the discovery of the FSHD candidate gene DUX4, many cell and animal models have been designed for therapeutic approaches and clinical trials. Today there is no treatment available for FSHD patients and therapeutic strategies targeting DUX4 toxicity in skeletal muscle are being actively investigated. In this review, we will discuss different research areas that are currently being considered to alter DUX4 expression and toxicity in muscle tissue and the cell and animal models designed to date.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD, OMIM: 158900, 158901) is one of the most common hereditary muscular dystrophies after Duchenne (DMD) and myotonic dystrophies
A few double homeobox 4 (DUX4) targets, such as ZSCAN4, are apparently insensitive to iP300w, indicating that an alternative regulation may occur. This is important because the DUX4 targets that are directly implicated in FSHD pathogenesis are not well-characterized and DUX4-network genes are often used as a biomarker of DUX4 activity, regardless of their physiological role and impact
Preclinical tests still remain a major condition to proceed with clinical trials and the design of a model that would recapitulate FSHD clinical signs is a major goal
Summary
Facioscapulohumeral muscular dystrophy (FSHD, OMIM: 158900, 158901) is one of the most common hereditary muscular dystrophies after Duchenne (DMD) and myotonic dystrophies. The high level of hypomethylation [15] associated with an opened chromatin structure due to repeat-contraction, leads to the derepression of DUX4 in skeletal muscle and the progression of clinical FSHD symptoms. This DUX4 expression is observed in the remaining 5% of FSHD patients (termed FSHD2) who, unlike FSHD1 patients, present a demethylation of the D4Z4 array of both alleles of chromosomes 4 and 10 [15,16] due to mutations in epigenetic repressors including the structural maintenance chromosome flexible hinge domain containing 1 (SMCHD1) [17] or the DNA methyltrasferase 3B (DNMT3B) genes [18]. The identification of DUX4 has led to the development of various animal and cell models, ranging from immortalized FSHD muscle cells to xenograft models, each having advantages and disadvantages over the others
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