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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2014
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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. |
format | Online Article Text |
id | pubmed-4165597 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
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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