Genomic stop codon scanning reveals quantitative principles of nonsense-mediated mRNA decay.

ABSTRACT: Nonsense-mediated mRNA decay (NMD) degrades transcripts containing premature termination codons (PTCs), critically shaping the disease outcomes of protein-truncating variants. While existing NMD rules categorize PTCs as NMD-triggering or NMD-evading, they cannot quantitatively predict the degree of NMD activity for a given endogenous PTC variant. To provide quantitative insight into NMD, we used saturation genome editing (SGE) to systematically introduce all possible PTCs (TAA, TAG, TGA) at every codon position spanning the first, penultimate, and three internal exons of the Lamin A/C (LMNA) gene. Combining targeted sequencing with NMD inhibition, we measured mRNA expression and NMD activity for 722 PTCs and 211 single nucleotide variants (SNVs). Our data validate known positional t

SUBMITTER: Cortazar MA 

PROVIDER: S-EPMC12776119 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature