Translational readthrough induction of pathogenic nonsense mutations

doi:10.1016/j.ejmg.2006.04.003

European Journal of Medical Genetics

Volume 49, Issue 6, November–December 2006, Pages 445-450

https://doi.org/10.1016/j.ejmg.2006.04.003 Get rights and content

Abstract

The treatment of genetic disorders is one of the biggest challenges lying ahead of modern medicine. While major advancements have been made in gene therapy, it is still far from achieving clinical success. However, other potential methods for treating single gene related diseases have also emerged recently. One such approach is the suppression of pathogenic nonsense mutations through inducing translational readthrough of the in-frame premature stop mutation. Aminoglycosides were the first drugs that gave promising results in this respect. This report provides a brief overview on the past, present and potential future of this pharmacogenetic approach.

Introduction

There are more than 1800 distinctly inherited human genetic disorders where nonsense mutations (in-frame, single-point alterations in the genetic code that prematurely stop the translation process of proteins producing non-functional, shortened molecules) cause disease in an appreciable percentage of patients [1]. This holds true for many forms of cancer as well. Examples include Duchenne muscular dystrophy (DMD, MIM #310200) and cystic fibrosis (CF, MIM #219700) that are among the most common genetic disorders, where ~10–20%, or ~10% of patients, respectively, carry nonsense mutations in the pathogenic gene [7], [34]. Pathogenic nonsense mutations may be as common as 70% in some human disorders, like in mucopolysaccharidosis type I (MIM #607014) for example [14].

There are two approaches currently to directly overcome disease caused by nonsense mutations. Gene therapy is a potential method, but despite of definite advancements it is still far from achieving clinical success [31]. The other approach aims to decrease the effects of a nonsense mutation by modifying gene expression. The strategy is to suppress the effects of the premature nonsense codon; in other words, to induce translational readthrough. This may be achieved by two distinct mechanisms. First, by decreasing the accuracy of translation elongation; second, by reducing the efficacy of the translation termination machinery [35]. In the past few decades it has been realized that aminoglycoside antibiotics can decrease the fidelity of the eukaryotic elongation machinery [19]. Consequently, this drug group may hold a valuable potential in the pharmacogenetic therapy of nonsense mutation related genetic disorders. This work intends to give a brief overview on aminoglycosides as pharmacogenetic agents and to highlight the clinical prospects of readthrough induction.

Section snippets

Aminoglycosides as translational readthrough inducing agents

Aminoglycosides inhibit prokaryotic protein synthesis at appropriate (“therapeutic”) concentrations. However, when applied at microbiologically sub-lethal levels some may induce incorporation of the wrong amino acid (mis-incorporation) at a sense codon or the insertion of an amino acid at a stop codon (leading to translational readthrough) [8], [13]. Similar aminoglycoside effects have been demonstrated in eukaryotic, even human cells but at concentrations 10–15 times higher than in prokaryotes

Conclusion

The studies above clearly demonstrate that a wide variety of targets may be present in the translation termination network for pharmacogenetic therapy that may utilize versatile molecules to suppress the expression of pathogenic nonsense mutations. While a major breakthrough in clinical gene therapy is awaited, pharmacogenetic methods may provide significant value in treating monogenic human disorders. Therefore, translational readthrough induction is a promising method of therapy in genetic

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ReviewTranslational readthrough induction of pathogenic nonsense mutations

Abstract

Introduction

Section snippets

Aminoglycosides as translational readthrough inducing agents

Conclusion

J. Mol. Biol.

Mol. Genet. Metab.

FEBS Lett.

J. Invest. Dermatol.

Biochim. Biophys. Acta

Trends Biochem. Sci.

J. Dermatol. Sci.

J. Mol. Biol.

Deficiency of polycystin-2 reduces Ca2+ channel activity and cell proliferation in ADPKD lymphoblastoid cells

FASEB J.

Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice

J. Biochem. (Tokyo)

Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin

Nucleic Acids Res.

Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics

Nature

Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis

Am. J. Respir. Crit. Care Med.

W. Gilbert, L. Gorini. Streptomycin, suppression, and the code

Proc. Natl. Acad. Sci. USA

Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Delta 48-50 DMD cells

Proc. Natl. Acad. Sci. USA

Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model

Proc. Natl. Acad. Sci. USA

Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle

Muscle Nerve

Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide

J. Gene Med.

Lack of fidelity in the translation of synthetic polyribonucleotides

Proc. Natl. Acad. Sci. USA

Review
Translational readthrough induction of pathogenic nonsense mutations

Deficiency of polycystin-2 reduces Ca²⁺ channel activity and cell proliferation in ADPKD lymphoblastoid cells