Nonsense codons that prematurely terminate translation generate potentially deleterious truncated proteins. Here, we show that the T cell receptor-beta (TCRbeta) gene, which acquires in-frame nonsense codons at high frequency during normal lymphocyte development, gives rise to an alternatively spliced transcript [alternative messenger RNA (alt-mRNA)] that skips the offending mutations that generate such nonsense codons. This alt-mRNA is up-regulated by a transfer RNA-dependent scanning mechanism that responds specifically to mutations that disrupt the reading frame. The finding that translation signals regulate the levels of alternatively spliced mRNAs generated in the nucleus may alter the current view of how gene expression is controlled in eukaryotic cells.