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Translation from a ...
Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice
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Wein, Nicolas (author)
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Vulin, Adeline (author)
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Falzarano, Maria S. (author)
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- Szigyarto, Christina Al-Khalili (author)
- KTH,Proteomik och nanobioteknologi
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Maiti, Baijayanta (author)
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Findlay, Andrew (author)
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Heller, Kristin N. (author)
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- Uhlén, Mathias (author)
- KTH,Proteomik och nanobioteknologi
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Bakthavachalu, Baskar (author)
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Messina, Sonia (author)
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Vita, Giuseppe (author)
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Passarelli, Chiara (author)
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Gualandi, Francesca (author)
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Wilton, Steve D. (author)
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Rodino-Klapac, Louise R. (author)
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Yang, Lin (author)
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- Dunn, Diane M. (author)
- Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, Utah, USA
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Schoenberg, Daniel R. (author)
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- Weiss, Robert B. (author)
- Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, Utah, USA
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Howard, Michael T. (author)
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Ferlini, Alessandra (author)
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Flanigan, Kevin M. (author)
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(creator_code:org_t)
- 2014-08-10
- 2014
- English.
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:9, s. 992-1000
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative, translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Wein, Nicolas
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Vulin, Adeline
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Falzarano, Maria ...
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Szigyarto, Chris ...
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Maiti, Baijayant ...
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Findlay, Andrew
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show more...
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Heller, Kristin ...
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Uhlén, Mathias
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Bakthavachalu, B ...
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Messina, Sonia
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Vita, Giuseppe
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Passarelli, Chia ...
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Gualandi, France ...
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Wilton, Steve D.
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Rodino-Klapac, L ...
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Yang, Lin
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Dunn, Diane M.
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Schoenberg, Dani ...
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Weiss, Robert B.
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Howard, Michael ...
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Ferlini, Alessan ...
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Flanigan, Kevin ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Nature Medicine
- By the university
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Royal Institute of Technology