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DMD transcript imbalance determines dystrophin levels.

Authors: Spitali, Pietro  van den Bergen, Janneke C  Verhaart, Ingrid E C  Wokke, Beatrijs  Janson, Anneke A M  van den Eijnde, Rani  den Dunnen, Johan T  Laros, Jeroen F J  Verschuuren, Jan J G M  't Hoen, Peter A C  Aartsma-Rus, Annemieke 
Citation: Spitali P, etal., FASEB J. 2013 Dec;27(12):4909-16. doi: 10.1096/fj.13-232025. Epub 2013 Aug 23.
Pubmed: (View Article at PubMed) PMID:23975932
DOI: Full-text: DOI:10.1096/fj.13-232025

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.

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CRRD Object Information
CRRD ID: 12879862
Created: 2017-04-28
Species: All species
Last Modified: 2017-04-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.