Arginine nonsense mutation (Arg-PTC)

An Arginine nonsense mutation is a specific genetic alteration where a codon encoding the amino acid arginine is converted into a premature termination codon (PTC), most frequently through a C-to-T transition at a CpG dinucleotide (e.g., CGA to UGA) (Linde & Kerem, 2008). This mutation results in the premature cessation of translation, leading to the production of truncated, non-functional proteins and the degradation of mRNA via nonsense-mediated decay (NMD) (Keeling et al., 2014). Arginine nonsense mutations are a significant cause of various hereditary diseases, including cystic fibrosis (e.g., the R553X mutation) and Duchenne muscular dystrophy, as well as many forms of cancer where they inactivate tumor suppressor genes like TP53 (Mort et al., 2008). As a therapeutic target, these mutations are addressed using "read-through" agents such as ataluren or specialized aminoglycosides like ELX-02 (Eloxx Pharmaceuticals, 2023). These drugs interact with the ribosome to decrease the fidelity of codon recognition at the PTC, allowing the incorporation of a near-cognate amino acid and the synthesis of a full-length, functional protein (PTC Therapeutics, 2024). Restoring even a small percentage of full-length protein can significantly alleviate disease symptoms and improve clinical outcomes for patients harboring these specific genetic lesions.

Other names

Arginine-to-stop mutationCGA-to-TGA mutationPremature termination codonPTCNonsense mutationRibosomal read-through target

Ribosomal read-through induction (suppression of premature termination codons by promoting the insertion of a near-cognate amino acid at the mutation site)