Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

• Widespread low-level expression of DUX4 from chrX causes male-specific lethality
• Retinal expression of DUX4 leads to retinal vascular pathology
• Low levels of DUX4 impair proliferation and differentiation of primary myoblasts
• Impaired regeneration by donor satellite cells provides a model for DUX4 pathology

SummaryFacioscapulohumeral muscular dystrophy (FSHD) is an enigmatic disease associated with epigenetic alterations in the subtelomeric heterochromatin of the D4Z4 macrosatellite repeat. Each repeat unit encodes DUX4, a gene that is normally silent in most tissues. Besides muscular loss, most patients suffer retinal vascular telangiectasias. To generate an animal model, we introduced a doxycycline-inducible transgene encoding DUX4 and 3′ genomic DNA into a euchromatic region of the mouse X chromosome. Without induction, DUX4 RNA was expressed at low levels in many tissues and animals displayed a variety of unexpected dominant leaky phenotypes, including male-specific lethality. Remarkably, rare live-born males expressed DUX4 RNA in the retina and presented a retinal vascular telangiectasia. By using doxycycline to induce DUX4 expression in satellite cells, we observed impaired myogenesis in vitro and in vivo. This mouse model, which shows pathologies due to FSHD-related D4Z4 sequences, is likely to be useful for testing anti-DUX4 therapies in FSHD.

Graphical AbstractFigure optionsDownload as PowerPoint slide