Change search
ReferencesLink to record
Permanent link

Direct link
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
Show others and affiliations
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.
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-153266DOI: 10.1038/nm.3628ISI: 000341404000011ScopusID: 2-s2.0-84908315048OAI: diva2:753848

QC 20141009

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

Open Access in DiVA

No full text

Other links

Publisher's full textScopus

Search in DiVA

By author/editor
Szigyarto, Christina Al-KhaliliUhlén, Mathias
By organisation
Proteomics and Nanobiotechnology
In the same journal
Nature Medicine
Cell and Molecular BiologyBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 19 hits
ReferencesLink to record
Permanent link

Direct link