Sense from nonsense: therapies for premature stop codon diseases.
Ten percent of inherited diseases are caused by premature termination codon (PTC) mutations that lead to degradation of the mRNA template and to the production of a non-functional, truncated polypeptide. In addition, many acquired mutations in cancer introduce similar PTCs. In 1999, proof-of-concept for treating these disorders was obtained in a mouse model of muscular dystrophy, when administration of aminoglycosides restored protein translation by inducing the ribosome to bypass a PTC. Since, many studies have validated this approach, but despite the promise of PTC readthrough therapies, the mechanisms of translation termination remain to be precisely elucidated before even more progress can be made. Here, we review the molecular basis for PTC readthrough in eukaryotes and describe currently available compounds with significant therapeutic potential for treating genetic disorders and cancer.
Université Paris-Sud, Orsay, France.
Laure
L
Bidou
Valérie
V
Allamand
Jean-Pierre
JP
Rousset
Olivier
O
Namy
D000617:Aminoglycosides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D018389:Codon, Nonsense; D030342:Genetic Diseases, Inborn / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects; D010443:Peptide Chain Termination, Translational / Q000187:drug effects; D010454:Peptide Termination Factors / Q000737:chemistry / Q000378:metabolism; D020871:RNA Stability
D000617:Aminoglycosides; D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D010454:Peptide Termination Factors