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.
Finkel
Richard S
RS
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Finkel@email.chop.edu
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