title: High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations leading to ectopic expression of the transcription factor DUX4, and encompasses both muscle-related and non-muscle phenotypes. Mouse models bearing this gene represent valuable tools to investigate which pathologies are due to DUX4 expression, and how DUX4 leads to these pathologies. The iDUX4(2.7) mouse contains an X-linked doxycycline-inducible DUX4 gene that shows low level basal expression in the absence of doxycycline, leading to male lethality, generally in embryo, but always before 8 weeks of age. Here, we describe additional non-muscle phenotypes in this animal model. We find that iDUX4(2.7) female carriers are extremely hyperactive, spending large amounts of time ambulating and much less time resting. Rare 3-week old males, although hypophagic, runted and extremely fragile, are capable of high activity, but show periods of catatonic torpor in which animals appear dead and respiration is virtually absent. We also examine a non-muscle phenotype of interest to FSHD, high frequency hearing loss. We find that young iDUX4(2.7) females are significantly impaired in their ability to hear at frequencies above 8 kHz. These phenotypes make the iDUX4(2.7) mouse an attractive model in which to study non-muscle activities of DUX4.
authors.affiliation: Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.affiliation: Department of Biochemistry, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Perrin
authors.affiliation: Program in Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Cabelka
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Razzoli
authors.affiliation: Department of Biochemistry, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Ervasti
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolomucci
authors.affiliation: Program in Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Lowe
authors.affiliation: Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, 55455, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
mesh_terms: D000818:Animals; D001823:Body Composition / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005804:Genes, Lethal; D006316:Hearing Loss, High-Frequency / Q000235:genetics*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006948:Hyperkinesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012120:Respiration Disorders / Q000235:genetics; D012727:Sex Characteristics; D064348:Torpor / Q000235:genetics; D019076:Transgenes / Q000187:drug effects; D014960:X Chromosome / Q000235:genetics; D049951:X Chromosome Inactivation
chemical_list: D002843:Chromatin; C532958:Dux4 protein, mouse; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; D004318:Doxycycline