期刊
ORPHANET JOURNAL OF RARE DISEASES
卷 7, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1750-1172-7-58
关键词
NMD; nonsense mutation; readthrough; RNA; small molecules
资金
- Inserm Avenir program
- Association Francaise contre les Myopathies
- Vaincre la Mucoviscidose
- la Fondation pour la Recherche Medicale
- la Ligue Regionale du Nord-Pas-de-Calais contre le Cancer
- l'Institut Pasteur de Lille
- Inserm/Region Nord-Pas-de-Calais
- European Commission [LSHM-CT-2006-036825]
- ANR Genopath-INAFIB
- Duchenne Parent Project Netherlands
- CNRS
- INSERM
- University Pierre
- Marie Curie
- Parents Project of Monaco
- European Parent Project
- CF Research, Inc
- Pennsylvania CF, Inc.
Background: Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough. Methods: Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs. Results: We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional. Conclusions: As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations.
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