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
Affiliations
Abhijit Dandapat
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Darko Bosnakovski
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Lynn M. Hartweck
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Robert W. Arpke
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Kristen A. Baltgalvis
Program in Physical Medicine and Rehabilitation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
Derek Vang
Vascular Biology Center, Division of Hematology, Oncology, and Transplantation, Department of Medicine MMC 480, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455, USA
June Baik
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Radbod Darabi
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
Rita C.R. Perlingeiro
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
F. Kent Hamra
Department of Pharmacology, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Kalpna Gupta
Vascular Biology Center, Division of Hematology, Oncology, and Transplantation, Department of Medicine MMC 480, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455, USA
Dawn A. Lowe
Program in Physical Medicine and Rehabilitation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
Michael Kyba
Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA
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.
