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

• DOI: 10.1016/j.celrep.2014.07.056
• Publication Date: 2014-08-28T19:55:16Z
• Authors: Abhijit Dandapat; Darko Bosnakovski; Lynn M. Hartweck; Robert W. Arpke; Kristen A. Baltga...; Derek Vang; June Baik; Radbod Darabi; Rita C.R. Perling...; F. Kent Hamra; Kalpna Gupta; Dawn A. Lowe; Michael Kyba
• Keywords: Facioscapulohumeral muscular dystrophy; Euchromatin

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