Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene

Dandapat, Abhijit and Bosnakovski, Darko and Hartweck, Lynn M. and Arpke, Robert and Baltgalvis, Kristen and Vang, Derek and Baik, June and Darabi, Radbod and Perlingeiro, Rita C. R. and Hamra, Kent and Gupta, Kapil and Lowe, Dawn and Kyba, Michael (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Reports, 8. pp. 1484-1496.

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Facioscapulohumeral 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.

Item Type: Article
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Health biotechnology
Divisions: Faculty of Medical Science
Depositing User: Darko Bosnakovski
Date Deposited: 04 Feb 2015 11:14
Last Modified: 04 Feb 2015 11:14

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