biostudies-literatureSpecht CNational Center for Advancing Translational SciencesCatherine Peachy Foundation Breast Cancer BreakthroughNCATS NIH HHSNational Institutes of HealthIU Simon Comprehensive Cancer CenterRiley Children’s FoundationIndiana University School of MedicineCystic Fibrosis FoundationIUSCCC Vera BradleyRiley Children's FoundationUniversity of ConnecticutIndiana Clinical and Translational Sciences InstituteNational Cancer InstituteNCI NIH HHSClinical and Translational Sciences AwardNIH HHSNIGMS NIH HHSgkaf532https://www.ebi.ac.uk/biostudies/studies/S-EPMC12204705biostudies-literatureUnknown53(12)Nonsense mutations that introduce premature termination codons (PTCs) into protein-coding genes are responsible for numerous genetic diseases; however, there are currently no effective treatment options for individuals affected by these mutations. One approach to combat nonsense-related diseases relies on the use of engineered suppressor transfer RNAs (sup-tRNAs) that facilitate translational stop codon readthrough, thereby restoring full-length protein synthesis. While several sup-tRNAs have shown promising results in preclinical models, many exhibit low PTC suppression efficiency, precluding their use as therapeutics. For example, glutamic acid (Glu) codons represent one of the most common sites for nonsense mutations, yet existing sup-tRNAs are ineffective at suppressing Glu-to-Stop mutNucleic acids researchAn engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.PMC12204705Department of Biochemistry and Molecular BiologyP30CA082709HUANG20F5P30 CA082709R35 GM146883UL1 TR002529R35GM146883UL1TR002529Tapia AVargas-Rodriguez OTharp JMSpecht CPenrod SHuang YAwawdeh AWhite CABeaudoin JDDoud EHSoriano GAAlshawi SAfalseAn engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.Nonsense mutations that introduce premature termination codons (PTCs) into protein-coding genes are responsible for numerous genetic diseases; however, there are currently no effective treatment options for individuals affected by these mutations. One approach to combat nonsense-related diseases relies on the use of engineered suppressor transfer RNAs (sup-tRNAs) that facilitate translational stop codon readthrough, thereby restoring full-length protein synthesis. While several sup-tRNAs have shown promising results in preclinical models, many exhibit low PTC suppression efficiency, precluding their use as therapeutics. For example, glutamic acid (Glu) codons represent one of the most common sites for nonsense mutations, yet existing sup-tRNAs are ineffective at suppressing Glu-to-Stop mut2025-01-01T00:00:00Z2025 Jun2026-06-01T15:59:41.642Z2026-04-08T13:56:04.429ZS-EPMC122047054053951310.1093/nar/gkaf532