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

doi:10.1016/j.celrep.2014.07.056

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 journal › Article › peer-review

59 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 language	English (US)
Pages (from-to)	1484-1496
Number of pages	13
Journal	Cell reports
Volume	8
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2014.07.056
State	Published - 2014

Bibliographical note

Funding 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.

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© 2014 The Authors.

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@article{db83556b81cf46009fb6eac19a3430b1,

title = "Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene",

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.",

author = "Abhijit Dandapat and Darko Bosnakovski and Hartweck, {Lynn M.} and Arpke, {Robert W.} and Baltgalvis, {Kristen A.} and Derek Vang and June Baik and Radbod Darabi and Perlingeiro, {Rita C R} and Hamra, {F. Kent} and Kalpna Gupta and Lowe, {Dawn A.} and Michael Kyba",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

doi = "10.1016/j.celrep.2014.07.056",

language = "English (US)",

volume = "8",

pages = "1484--1496",

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T1 - Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

AU - Dandapat, Abhijit

AU - Bosnakovski, Darko

AU - Hartweck, Lynn M.

AU - Arpke, Robert W.

AU - Baltgalvis, Kristen A.

AU - Vang, Derek

AU - Baik, June

AU - Darabi, Radbod

AU - Perlingeiro, Rita C R

AU - Hamra, F. Kent

AU - Gupta, Kalpna

AU - Lowe, Dawn A.

AU - Kyba, Michael

N1 - Funding 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. Publisher Copyright: © 2014 The Authors.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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JO - Cell reports

JF - Cell reports

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ER -

Dominant Lethal Pathologies in Male Mice Engineered to Contain an X-Linked DUX4 Transgene

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