Read-through strategies for suppression of nonsense mutations in Duchenne/ Becker muscular dystrophy: aminoglycosides and ataluren (PTC124).
Nucleotide changes within an exon can alter the trinucleotide normally encoding a particular amino acid, such that a new ''stop'' signal is transcribed into the mRNA open reading frame. This causes the ribosome to prematurely terminate its reading of the mRNA, leading to nonsense-mediated decay of the transcript and lack of production of a normal full-length protein. Such premature termination codon mutations occur in an estimated 10% to 15% of many genetically based disorders, including Duchenne/Becker muscular dystrophy. Therapeutic strategies have been developed to induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein. Small-molecule drugs (aminoglycosides and ataluren [PTC124]) have been developed and are in clinical testing in patients with nonsense mutations within the dystrophin gene. Use of nonsense mutation suppression in Duchenne/Becker muscular dystrophy may offer the prospect of targeting the specific mutation causing the disease and correcting the fundamental pathophysiology.
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Finkel@email.chop.edu
Richard S
RS
Finkel
D000617:Aminoglycosides / Q000627:therapeutic use*; D002648:Child; D018389:Codon, Nonsense / Q000187:drug effects* / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000517:prevention & control*; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics* / Q000517:prevention & control; D010069:Oxadiazoles / Q000627:therapeutic use*; D013489:Suppression, Genetic / Q000187:drug effects* / Q000235:genetics
D000617:Aminoglycosides; D018389:Codon, Nonsense; D010069:Oxadiazoles; C515878:ataluren