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Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases

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Abstract Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in‐frame premature termination codons (PTCs) to restore translation of a full‐length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense‐mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy. WIREs RNA 2011 2 837–852 DOI: 10.1002/wrna.95 Correction added on July 13 2011, after first online publication. Figure 5 was incorrect and has been replaced. This article is categorized under: Translation > Translation Mechanisms RNA in Disease and Development > RNA in Disease

Suppression of translation termination. During the suppression of a premature stop codon, a near‐cognate aminoacyl tRNA pair at two of the three bases of the stop codon. The amino acid carried by the near‐cognate tRNA is added to the polypeptide chain and translation resumes in the proper reading frame until the natural stop codon is reached.

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Translation termination. During translation termination, eukaryotic release factors 1 and 3 (eRF1 and eRF3) bind the pretermination complex with a stop codon located in the ribosomal A site. eRF1 mediates the initial recognition of the stop codon. GTP hydrolysis by eRF3 finalizes stop codon recognition and facilitates polypeptide chain release.

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Structure of the nonsense‐mediated mRNA decay (NMD) inhibitor, NMDI‐1.

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A simplified model of mammalian nonsense‐mediated mRNA decay (NMD).

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Structures of non‐aminoglycoside compounds that suppress translation termination at premature termination codons.

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Structures of conventional aminoglycosides and novel synthetic aminoglycosides. The novel synthetic aminoglycoside derivatives shown contain structural components of conventional aminoglycosides (shaded and labeled (A)–(C)) that are predicted to enhance suppression nonsense mutations while decreasing their nonspecific interactions.

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Structures of gentamicin congeners.

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Comparison of translation termination at natural versus premature stop codons. (a) Termination at natural stop codons. Termination efficiency at natural stop codons located near the 3′ end of mRNAs is enhanced by interactions between eukaryotic release factor 3 (eRF3) and poly(A) binding protein (PABP). (b) Termination at premature stop codons. eRF3 and PABP cannot interact efficiently because of the spatial distance between premature termination codons and the poly(A) tail of the mRNA where PABP binds, thus reducing the efficiency of termination. The absence of this interaction is thought to result in ribosome pausing at the premature stop codon, making them more susceptible to suppression.

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