Nonsense-associated alternative splicing of T-cell receptor beta genes: no evidence for frame dependence

Mutations that generate premature translation-termination codons (PTCs) often result in production of alternatively spliced mRNAs. While in many cases, the PTC-causing mutation was found to affect splicing directly by disrupting an exonic splicing enhancer, induction of alternative splicing of TCR-beta pre-mRNA has been reported to be specific for mutations that prematurely terminate the open reading frame. During testing of a cyto-nuclear feedback model that would have explained how cytoplasmic translation could influence nuclear splicing of TCR-beta transcripts, control experiments questioned the frame dependence of the nonsense-associated altered splicing (NAS) of TCR-beta pre-mRNA. A subsequent detailed analysis of alternatively spliced TCR-beta mRNA expressed from different minigene constructs with nonsense, silent, or frame-shift mutations at various positions revealed no correlation between truncation of the reading frame and production of alternatively spliced mRNA. Our study thus contradicts the previously reported PTC specificity of TCR-beta NAS and points out the need for systematically testing the PTC specificity in other cases where NAS has been observed.