Premature stop codons in mRNA of disease-associated genes (PTCs)

Premature stop codons (PTCs) are genetic mutations that introduce a termination signal (UAA, UAG, or UGA) within the coding region of a messenger RNA (mRNA) molecule, leading to the production of truncated, non-functional proteins (PMID: 22446953). These mutations are estimated to cause approximately 10% to 15% of all inherited human diseases, including cystic fibrosis and Duchenne muscular dystrophy (Nature Reviews Drug Discovery, 2014). Beyond producing incomplete proteins, PTCs often trigger nonsense-mediated mRNA decay (NMD), a cellular surveillance mechanism that degrades the mutant mRNA, further reducing the levels of any potential protein product (NIH, 2020). Therapeutic strategies targeting PTCs focus on translational read-through, where small molecules interact with the ribosome to encourage the insertion of a near-cognate amino acid at the stop site, allowing the synthesis of a full-length, functional protein (PubChem, CID 11652416). Drugs like ataluren and certain aminoglycosides have been developed to exploit this mechanism, though challenges remain regarding the efficiency of read-through and the potential for off-target effects on natural termination codons (StatPearls, 2023). Additionally, the development of next-generation read-through agents like ELX-02 aims to improve the safety profile and efficacy for specific genetic conditions (ClinicalTrials.gov, NCT03464396). Monitoring the success of these therapies typically involves measuring the restoration of full-length protein expression or assessing the stability of the target mRNA (PMID: 31431664).

Other names

Nonsense mutationsPremature termination codonsPTCIn-frame stop codons

Translational read-through (nonsense suppression) and inhibition of nonsense-mediated mRNA decay (NMD)