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.
Bibliographical noteFunding Information:
This project was primarily supported by grants from the NIH (R01 AR055685), the Dr. Bob and Jean Smith Foundation, and the Friends of FSH Research to M.K. and the Muscular Dystrophy Centre Core Laboratory P30 AR0507220. D.B. was supported by a Muscular Dystrophy Association Development Grant (MDA 4361) and a Marjorie Bronfman Research Fellowship from the FSH Society (FSHS-MGBF-016). R.C.R.P. was supported by NIH grants R01 AR055299 and U01 HL100407. K.A.B. was supported by NIH grant T32-AR07612 and D.A.L. by K02-AG036827. K.G. and D.V. were supported by NIH grants R01 HL68802 and R01 HL103773. F.K.H. was supported by NIH grant R01 HD053889.
© 2014 The Authors.