This is for the naysayers! Jill you were right! :)
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Will exon skipping work for premature stop codons/nonsense mutations ? This seems like a dumb question after being well-involved in Duchenne research, but I am still not sure ? Anyone know the answer to this ?
Don't worry, there are no dumb questions, Tamara. I think the answer ought be: quite possibly. The idea is to bypass the exon where the mutation lives, creating a shorter, but hopefully functional form of dystrophin. This is theoretically an approach that'd address quite a number of the mutation types, including nonsense mutations.
There may be a hitch for our sons here, though. As far as I've been able to tell, if the body has never produced dystrophin (which might be the case for nonsense-mutations) - the body might not recognize this new shortened dystrophin protein as normal and might essentially attack it (re: immune response) thereby degrading or negating the benefit. There's a lot of immunological work being done here that goes way over my head.
-Dave
Tamara Walters said:Will exon skipping work for premature stop codons/nonsense mutations ? This seems like a dumb question after being well-involved in Duchenne research, but I am still not sure ? Anyone know the answer to this ?
Thanks. I understand exon skipping as a way to "patch" a deletion, but since we are dealing with point mutations as opposed to deletions, I do not know for sure...
If you are able to skip the whole exon the error being the false stop codon should just be skipped . So in principle - to my understanding- exon skipping can also work for this cases if the Exon can be skipped safely.
Tamara Walters said:Thanks. I understand exon skipping as a way to "patch" a deletion, but since we are dealing with point mutations as opposed to deletions, I do not know for sure...
Ok in a nutshell exon skipping does work for non-sense mutations as it removes the stop codon from the sequence. However for the exon skip to work there are a number of factors involved.
- The location of the non-sense mutation. This is important as if it is in the wrong place it can interfer with the splicing motifs or whatever they are called.
- The exon you want skipped and how it fits into the exon after and before it. In a lot of cases it will be a straight single exon skip, but in some cases it may take more than one exon to be skipped to join up the exons after the splicing. I used to have an order which showed how the exons fitted into each other ( ie 1> >2 > >34| |5 ) etc, but I dont know where to find it now.
The problem then becomes actually getting someone to make the compound to skip a specific exon as they are only concentrating on the groups where it will benifit the most people as it gives them the most data for trials which is understandable however still frustarting.
My understanding is that all the other compounds HAVE now been created in the lab (Steve Wilton's been working on this I believe).
Jonathan said:Ok in a nutshell exon skipping does work for non-sense mutations as it removes the stop codon from the sequence. However for the exon skip to work there are a number of factors involved.
- The location of the non-sense mutation. This is important as if it is in the wrong place it can interfer with the splicing motifs or whatever they are called.
- The exon you want skipped and how it fits into the exon after and before it. In a lot of cases it will be a straight single exon skip, but in some cases it may take more than one exon to be skipped to join up the exons after the splicing. I used to have an order which showed how the exons fitted into each other ( ie 1> >2 > >34| |5 ) etc, but I dont know where to find it now.
The problem then becomes actually getting someone to make the compound to skip a specific exon as they are only concentrating on the groups where it will benifit the most people as it gives them the most data for trials which is understandable however still frustarting.
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