A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations

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 can result from alternate translation initiation beginning in DMD exon 6 that leads to expression of a highly function...

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Autores principales: Wein, Nicolas, Vulin, Adeline, Sofia Falzarano, Maria, Al-Khalili Szigyarto, Christina, Maiti, Baijayanta, Findlay, Andrew, Heller, Kristin N, Uhlén, Mathias, Bakthavachalu, Baskar, Messina, Sonia, Vita, Giuseppe, Passarelli, Chiara, Gualandi, Francesca, Wilton, Steve D, Rodino-Klapac, Louise, Yang, Lin, Dunn, Diane M., Schoenberg, Daniel, Weiss, Robert B., Howard, Michael T., Ferlini, Alessandra, Flanigan, Kevin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165597/
https://www.ncbi.nlm.nih.gov/pubmed/25108525
http://dx.doi.org/10.1038/nm.3628
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author Wein, Nicolas
Vulin, Adeline
Sofia Falzarano, Maria
Al-Khalili Szigyarto, Christina
Maiti, Baijayanta
Findlay, Andrew
Heller, Kristin N
Uhlén, Mathias
Bakthavachalu, Baskar
Messina, Sonia
Vita, Giuseppe
Passarelli, Chiara
Gualandi, Francesca
Wilton, Steve D
Rodino-Klapac, Louise
Yang, Lin
Dunn, Diane M.
Schoenberg, Daniel
Weiss, Robert B.
Howard, Michael T.
Ferlini, Alessandra
Flanigan, Kevin M.
author_facet Wein, Nicolas
Vulin, Adeline
Sofia Falzarano, Maria
Al-Khalili Szigyarto, Christina
Maiti, Baijayanta
Findlay, Andrew
Heller, Kristin N
Uhlén, Mathias
Bakthavachalu, Baskar
Messina, Sonia
Vita, Giuseppe
Passarelli, Chiara
Gualandi, Francesca
Wilton, Steve D
Rodino-Klapac, Louise
Yang, Lin
Dunn, Diane M.
Schoenberg, Daniel
Weiss, Robert B.
Howard, Michael T.
Ferlini, Alessandra
Flanigan, Kevin M.
author_sort Wein, Nicolas
collection PubMed
description 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 can result from alternate translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. This novel isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid-inducible. IRES activity is confirmed in patient muscle by both peptide sequencing and ribosome profiling. Generation of a truncated reading frame upstream of the IRES by exon skipping leads to synthesis of a functional N-truncated isoform in both patient-derived cell lines and in a new DMD mouse model, where expression protects muscle from contraction-induced injury and corrects muscle force to the same level as control mice. These results support a novel therapeutic approach for patients with mutations within the 5’ exons of DMD.
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spelling pubmed-41655972015-03-01 A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations Wein, Nicolas Vulin, Adeline Sofia Falzarano, Maria Al-Khalili Szigyarto, Christina Maiti, Baijayanta Findlay, Andrew Heller, Kristin N Uhlén, Mathias Bakthavachalu, Baskar Messina, Sonia Vita, Giuseppe Passarelli, Chiara Gualandi, Francesca Wilton, Steve D Rodino-Klapac, Louise Yang, Lin Dunn, Diane M. Schoenberg, Daniel Weiss, Robert B. Howard, Michael T. Ferlini, Alessandra Flanigan, Kevin M. Nat Med Article 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 can result from alternate translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. This novel isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid-inducible. IRES activity is confirmed in patient muscle by both peptide sequencing and ribosome profiling. Generation of a truncated reading frame upstream of the IRES by exon skipping leads to synthesis of a functional N-truncated isoform in both patient-derived cell lines and in a new DMD mouse model, where expression protects muscle from contraction-induced injury and corrects muscle force to the same level as control mice. These results support a novel therapeutic approach for patients with mutations within the 5’ exons of DMD. 2014-08-10 2014-09 /pmc/articles/PMC4165597/ /pubmed/25108525 http://dx.doi.org/10.1038/nm.3628 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wein, Nicolas
Vulin, Adeline
Sofia Falzarano, Maria
Al-Khalili Szigyarto, Christina
Maiti, Baijayanta
Findlay, Andrew
Heller, Kristin N
Uhlén, Mathias
Bakthavachalu, Baskar
Messina, Sonia
Vita, Giuseppe
Passarelli, Chiara
Gualandi, Francesca
Wilton, Steve D
Rodino-Klapac, Louise
Yang, Lin
Dunn, Diane M.
Schoenberg, Daniel
Weiss, Robert B.
Howard, Michael T.
Ferlini, Alessandra
Flanigan, Kevin M.
A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title_full A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title_fullStr A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title_full_unstemmed A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title_short A novel DMD IRES results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
title_sort novel dmd ires results in a functional n-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165597/
https://www.ncbi.nlm.nih.gov/pubmed/25108525
http://dx.doi.org/10.1038/nm.3628
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