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Pharmacological Suppression of Premature Stop Mutations that Cause Genetic Diseases

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Aminoglycoside antibiotics have long been used as antibacterial agents due to their ability to inhibit bacterial translation. However, aminoglycosides also stimulate translation errors in mammalian cells. Aminoglycosides bind to a pocket formed in a domain of the ribosomal RNA (rRNA) of the small ribosomal subunit that constitutes the decoding site in both prokaryotes and eukaryotes. Normally, accurate base pairing takes place between each successive codon and its cognate aminoacyl-tRNA within this region of the ribosome. When aminoglycosides bind to the decoding site, a conformational change decreases discrimination between cognate and near-cognate tRNAs, leading to errors in the decoding process. The ability of aminoglycosides to bind to the decoding site and induce translational misreading in eukaryotic cells is less efficient than in prokaryotic cells due to subtle differences in the sequence of the decoding site rRNA. The observation that aminoglycosides induce low levels of misreading in eukaryotic cells has inspired many investigations to determine whether aminoglycosides can suppress nonsense mutations that cause human diseases. Disease models in which aminoglycosides have been shown to efficiently suppress nonsense mutations include cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome, infantile neuronal lipfuscinosis, cystinosis, x-linked nephrogenic insipidus, spinal muscular atrophy, and cancer. However, if aminoglycosides are to be used clinically for suppression therapy, their efficacy must be improved and their toxicity reduced. The co-administration of other compounds that reduce aminoglycoside toxicity or the development of new compounds that suppress stop mutations may allow the realization of suppression therapy as a clinical treatment to suppress disease-causing stop mutations.
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Keywords: Cystic fibrosis (CF); Duchenne muscular dystrophy (DMD); aminoglycosides; bacterial 70S ribosome; cognate tRNAs; fatty acid binding protein promoter (FABP)

Document Type: Review Article

Affiliations: Department of Microbiology, BBRB 432/Box 8, 1530 Third Avenue, South, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.

Publication date: December 1, 2005

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  • Current Pharmacogenomics provides comprehensive overviews of all current research on pharmacogenomics and pharmacogenetics. All areas of the field from pre-clinical to clinical research are covered, including related areas such as genomics, proteomics, target discovery, bioinformatics and novel diagnostics. This international journal is peer-reviewed and publishes both mini- and full review articles.

    The journal has become essential reading for all researchers and clinicians with interests in pharmacogenomics and pharmacogenetics.
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