They had suggested that a fraction of the mutant transcripts encoded a non-functional RPN12A-NPTII fusion protein that, upon insertion into the proteasome, altered its activity.
In CAG repeat expansion diseases, the presence of coding mutation may confer toxicity to the mutant transcripts and to encoded poly-Q proteins.
Conceptual translation of new transcript encodes a protein (Bax-α1), having different N-terminus.
A third transcript encodes a homologue to an Ectocarpus glucosylceramidase.
The additional essential transcript encodes a phosphoserine phosphatase.
There was a clear reduction in the levels of mutant transcripts compared to wild-type; we determined that transcripts encoding p.L145X were present at 43.8% ± 8.2% (standard error of the mean) of the level of wild-type transcripts, suggesting that the p.L145X allele also confers transcript instability.
Unlike kinase inhibitors, which generally block ATP-dependent enzymatic activity, ASOs bind to and downregulate transcripts encoding any chosen gene product, including "non-druggable" targets (e.g., adaptor molecules, transcription factors, or cancer-specific mutant transcripts) [ 24, 25].
Mutations in BAX, MSH3 and CASP5 all encode for NMD-sensitive (NMD-S) mutant transcripts; mutant BAX and MSH3 are known to be susceptible to degradation[27].
For example, the clearance of mutant transcripts by NMD may reduce disease severity by eliminating transcripts that encode proteins with dominant-negative effects.
In contrast, we found no discernable difference in the amount of transcript encoding VTI11 or VTI12, two other VTI family members, in the vti13 mutant (Fig. 1A, Table 1).
