Nonsense mutation (PTC)

Nonsense mutations are point mutations in DNA that result in a premature stop codon (UAA, UAG, or UGA) in the transcribed mRNA. This premature termination codon (PTC) signals the ribosome to stop translation early, leading to the production of truncated, non-functional proteins or the degradation of the mRNA through a process called nonsense-mediated decay (NMD) [1]. These mutations are a significant cause of genetic disorders, contributing to roughly 11% of all described gene lesions causing human inherited disease [2]. Therapeutic approaches, often referred to as "nonsense suppression therapy," utilize small molecules known as read-through agents to modulate the ribosome's fidelity [3]. These agents, such as ataluren or certain aminoglycosides, encourage the ribosome to skip the PTC and insert a near-cognate tRNA, allowing the synthesis of a full-length, functional protein [4]. Despite their potential, these therapies face hurdles including low read-through efficiency and the risk of suppressing natural termination codons, which could lead to cellular toxicity [5]. Sources: [1] https://www.ncbi.nlm.nih.gov/books/NBK21114/ [2] https://pubmed.ncbi.nlm.nih.gov/21900391/ [3] https://www.nature.com/articles/nrd.2017.93 [4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412126/ [5] https://pubmed.ncbi.nlm.nih.gov/24513171/

Other names

Premature termination codonPTCStop mutationPoint mutation (nonsense)

Ribosomal read-through of premature termination codons (PTCs) to restore full-length protein synthesis; Inhibition of nonsense-mediated mRNA decay (NMD).