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

Abhijit Dandapat, Darko Bosnakovski, Lynn M. Hartweck, Robert W. Arpke, Kristen A. Baltgalvis, Derek Vang, June Baik, Radbod Darabi, Rita C R Perlingeiro, F. Kent Hamra, Kalpna Gupta, Dawn A. Lowe, Michael Kyba

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) isan 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 invitro and invivo. This mouse model, which shows pathologies due to FSHD-related D4Z4 sequences, is likely to be useful for testing anti-DUX4 therapies in FSHD.

Original languageEnglish (US)
Pages (from-to)1484-1496
Number of pages13
JournalCell Reports
Volume8
Issue number5
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dandapat, A., Bosnakovski, D., Hartweck, L. M., Arpke, R. W., Baltgalvis, K. A., Vang, D., Baik, J., Darabi, R., Perlingeiro, R. C. R., Hamra, F. K., Gupta, K., Lowe, D. A., & Kyba, M. (2014). Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene. Cell Reports, 8(5), 1484-1496. https://doi.org/10.1016/j.celrep.2014.07.056