UGA premature termination codon in mRNA (UGA PTC)

A UGA premature termination codon (PTC) is a nonsense mutation in mRNA where the triplet sequence uracil-guanine-adenine appears prematurely in the open reading frame. In normal translation, UGA serves as a signal for the ribosome to cease protein synthesis; however, when it occurs prematurely, it leads to truncated, non-functional proteins and triggers nonsense-mediated mRNA decay (NMD), which significantly reduces mRNA levels (Linde and Kerem, 2008). This molecular defect is responsible for approximately 11% of all described gene lesions causing human inherited disease, including specific subsets of cystic fibrosis and Duchenne muscular dystrophy (Mort et al., 2008). Therapeutic interventions targeting UGA PTCs utilize \"read-through\" agents, such as ataluren or aminoglycoside derivatives, which interact with the ribosome to promote the insertion of a near-cognate amino acid at the PTC site (Welch et al., 2007). This allows the ribosome to bypass the premature stop signal and complete the synthesis of a full-length, functional protein, potentially modifying the course of the associated genetic disorder (Nagel-Wolfrum et al., 2016). Furthermore, the efficiency of read-through is often influenced by the surrounding nucleotide context, with the UGA codon generally being more susceptible to suppression than other stop codons (Keeling et al., 2014). Despite the potential, challenges remain regarding the toxicity of certain read-through agents and the risk of suppressing natural termination codons, which could lead to global proteomic instability.

Other names

UGA nonsense mutationOpal premature stop codonPremature termination codonUGA stop codon

Induction of translational read-through by binding to the ribosome and reducing the fidelity of codon-anticodon recognition at the premature stop site (Welch et al., 2007; Keeling et al., 2014).