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Lookup NU author(s): Dr Ingrid Verhaart, Professor Annemieke Aartsma-Rus
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Duchenne and Becker muscular dystrophies are caused by out-of-frame and in-frame mutations, respectively, in the dystrophin encoding DMD gene. Molecular therapies targeting the precursor-mRNA are in clinical trials and show promising results. These approaches will depend on the stability and expression levels of dystrophin mRNA in skeletal muscles and heart. We report that the DMD gene is more highly expressed in heart than in skeletal muscles, in mice and humans. The transcript mutated in the mdx mouse model shows a 5' to 3' imbalance compared with that of its wild-type counterpart and reading frame restoration via antisense-mediated exon skipping does not correct this event. We also report significant transcript instability in 22 patients with Becker dystrophy, clarifying the fact that transcript imbalance is not caused by premature nonsense mutations. Finally, we demonstrate that transcript stability, rather than transcriptional rate, is an important determinant of dystrophin protein levels in patients with Becker dystrophy. We suggest that the availability of the complete transcript is a key factor to determine protein abundance and thus will influence the outcome of mRNA-targeting therapies.
Author(s): Spitali P, van den Bergen JC, Verhaart IE, Wokke B, Janson AA, van den Eijnde R, den Dunnen JT, Laros JF, Verschuuren JJ, 't Hoen PA, Aartsma-Rus A
Publication type: Article
Publication status: Published
Journal: FASEB Journal
Year: 2013
Volume: 27
Issue: 12
Pages: 4909-4916
Print publication date: 01/12/2013
Online publication date: 23/08/2013
ISSN (print): 0892-6638
ISSN (electronic): 1530-6860
Publisher: Federation of American Societies for Experimental Biology
URL: http://www.fasebj.org/content/27/12/4909.full.pdf
DOI: 10.1096/fj.13-232025
PubMed id: 23975932
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