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 journalArticlepeer-review

46 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 - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene'. Together they form a unique fingerprint.

Cite this