The aim of exon skipping is to restore the genetic code so the correct protein subunits are used (instead of the aberrant subunits), to allow the synthesis of a partially functional proteins. This can be explained by look at a model car: a model car that has some parts missing is more useful than a model car with aberrant airplane parts. The reasoning for this approach is explained in detail in background of Duchenne muscular dystrophy.
Exon skipping can be used to restore the genetic code for different mutations types. The different mutation types are described in mutations.
The following figures contain three parts: at the top the situation at DNA level (so the level of the gene) is depicted, in the middle the RNA copy is shown (occasionally one of the exons is hidden by an AON). At the bottom the resulting mRNA (so only the genetic code (the exons) is shown.
To explain the exon skipping technique, the following figures contain three parts:
- Top row: the situation at DNA (gene) level
- Middle row: RNA copy before the introns are deleted, occassionally one or more exons hidden by an AON
- Bottom row: the resulting mRNA: the genetic code with all exons
For most deletions of one or more exons, the genetic code can be restored by the skipping of one (Figure 1) or two (Figure 2) exons.
Duplications disrupt the genetic code because one or more exons are duplicated. This complicates exon skipping, as the AONs can not distinguish the duplicated and the original exon (they are completely similar). For duplications involving a single exon, exon skipping can be used to restore the genetic code (Figures 3, 4 and 5). However, for larger duplications, exon skipping is currently too complicated (Figures 6, 7 and 8).
Figure 4 en 5 only contain the RNA copy and the resulting mRNA. For the situation at DNA level see Figure 3.
Figure 7 en 8 only contain the RNA copy and the resulting mRNA. For the situation at DNA level see Figure 6.
Small mutations can result in a premature stop signal (stop mutations), or they can disrupt the genetic code (a small deletion or duplication within and exon). Using exon skipping; these mutations can be bypassed (Figure 9 and 10).