DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD.

Keywords: cell death; double homeobox protein 4 (DUX4); embryonic gene expression; epigenetics; facioscapulohumeral muscular dystrophy; muscle differentiation; signalling; skeletal muscle; toxicity.

Figure 1

DUX4 signalling in FSHD-affected skeletal muscle. A simplified overview of the various signalling activities of DUX4 discussed in this review is depicted. Red arrows indicate a confirmed direct downstream DUX4 transcriptional target. Abbreviation: ROS, reactive oxygen species; FSHD facioscapulohumeral muscular dystrophy; DUX4: double homeobox protein 4.