Premature UGA termination codon (PTC) (PTC)

Premature UGA nonsense codons are genetic mutations where a sense codon is replaced by the UGA (opal) stop sequence, leading to the production of truncated, non-functional proteins and the degradation of mRNA via nonsense-mediated mRNA decay (NMD) (Linde & Kerem, 2008, Trends in Genetics). These mutations are a primary cause of various severe genetic disorders, including Duchenne muscular dystrophy and cystic fibrosis, where they account for a significant percentage of cases (Welch et al., 2007, Nature). As a therapeutic target, these codons are addressed by small-molecule "read-through" agents such as ataluren and ELX-02, which interact with the ribosome to decrease the fidelity of codon recognition specifically at the premature site (Keeling et al., 2014, Crit Rev Biochem Mol Biol). This interaction allows the insertion of a near-cognate amino acid, enabling the ribosome to bypass the premature stop and synthesize a full-length, functional protein (Nagai & Akizawa, 2020, Pharmaceutics). The efficacy of targeting UGA codons is often influenced by the surrounding nucleotide sequence, known as the "sequence context," which affects the baseline level of ribosomal "leakiness" (McCaughan et al., 1995, PNAS). While therapeutic suppression aims to restore protein function, a major challenge remains achieving high levels of read-through at the premature site without causing deleterious read-through at canonical stop codons (Brooks et al., 2006, Journal of Gene Medicine).

Other names

Premature UGA nonsense codonUGA stop codon mutationOpal nonsense mutationPremature termination codon

Induction of translational read-through by promoting the incorporation of near-cognate aminoacyl-tRNAs at the premature stop codon site, allowing the ribosome to continue translation to the original stop codon (Keeling et al., 2014, Crit Rev Biochem Mol Biol).