title: Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene.
abstract: 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.
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Darko
authors.initials: D
authors.lastname: Bosnakovski
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Hartweck
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Arpke
authors.affiliation: Program in Physical Medicine and Rehabilitation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Baltgalvis
authors.affiliation: 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.
authors.forename: Derek
authors.initials: D
authors.lastname: Vang
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Medicine, University of Minnesota, 312 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: June
authors.initials: J
authors.lastname: Baik
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Medicine, University of Minnesota, 312 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: Radbod
authors.initials: R
authors.lastname: Darabi
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Medicine, University of Minnesota, 312 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: Rita C R
authors.initials: RC
authors.lastname: Perlingeiro
authors.affiliation: 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.
authors.forename: F Kent
authors.initials: FK
authors.lastname: Hamra
authors.affiliation: 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.
authors.forename: Kalpna
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Program in Physical Medicine and Rehabilitation, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Lowe
authors.affiliation: Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA. Electronic address: kyba@umn.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D022041:Euchromatin / Q000235:genetics; D005799:Genes, Dominant; D050172:Genes, X-Linked; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology
chemical_list: C532958:Dux4 protein, mouse; D022041:Euchromatin; D018398:Homeodomain Proteins; D012333:RNA, Messenger