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Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.ORCID iD: 0000-0001-6990-1905
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2014 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 20, no 9, 992-1000 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 20, no 9, 992-1000 p.
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Cell and Molecular Biology Biochemistry and Molecular Biology
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URN: urn:nbn:se:kth:diva-153266DOI: 10.1038/nm.3628ISI: 000341404000011Scopus ID: 2-s2.0-84908315048OAI: oai:DiVA.org:kth-153266DiVA: diva2:753848
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QC 20141009

Available from: 2014-10-09 Created: 2014-10-03 Last updated: 2017-12-05Bibliographically approved

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Szigyarto, Christina Al-KhaliliUhlén, Mathias

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