Hello,

My boy got Stop Codon Mutation - Exon 16 (p.K632X). Any boy have same mutation ? Need yr advise.

Much thanks.

Trinh

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Hello,

my boy has also stop codon in exon 16

Dear Blazena,

Do you know current research for this mutation ?

Tks,

Trinh

Blazena Kaderabkova said:

Hello,

my boy htas also stop codon in exon 16

Dear Trinh,

I know about Ataluren - PTC124 for stop codon mutation.

Dear Blazena,

I checked this link : http://www.cureduchenne.org/site/PageServer?pagename=research_index#2 stop codon

Ataluren - PTC124 was terminated. Do you know ?

Trinh

Blazena Kaderabkova said:

Dear Trinh,

I know about Ataluren - PTC124 for stop codon mutation.

Much thanks Blazena.

I will read it.

Trinh

Based on this chart:

http://www.actionduchenne.org/duchennepedia/article/15/exon-skipping

skipping exon 16 would produce an in-frame dystrophin transcript.  Therefore a steric-blocking antisense oligo (such as a 2'-O-MePS or Morpholino oligo) would be a reasonable treatment candidate for that mutation.  However, as far as I know there is no preclinical development ongoing for an oligo targeting that exon.  In the future, that might end up being the preferred treatment as it would be likely to produce functional dystrophin.

 

Note - the way you interpret the chart is to find the exon to delete and look at the shape of the nearest ends of the adjacent exons.  Since the right side of exon 15 matches up with the left side of exon 17, removing exon 16 would produce an in-frame transcript.  You can also use the chart to predict the exon skip needed for an exon-deletion mutation.  For instance, if someone has a deletion of exon 52 and you administer an oligo to skip exon 51, the right side of exon 53 fits like a puzzle piece with the left side of exon 50.  That shows that the transcript missing exons 51 (by oligo) and 52 (by mutation) would produce an in-frame dystrophin transcript.

Dear Jon,

Very much thanks for yr explanation. I have learnt a lot from that. In case of my son, removing exon 16 would produce an in-frame transcript.

Again, thanks.

Trinh

Jon Moulton said:

Based on this chart:

http://www.actionduchenne.org/duchennepedia/article/15/exon-skipping

skipping exon 16 would produce an in-frame dystrophin transcript.  Therefore a steric-blocking antisense oligo (such as a 2'-O-MePS or Morpholino oligo) would be a reasonable treatment candidate for that mutation.  However, as far as I know there is no preclinical development ongoing for an oligo targeting that exon.  In the future, that might end up being the preferred treatment as it would be likely to produce functional dystrophin.

 

Note - the way you interpret the chart is to find the exon to delete and look at the shape of the nearest ends of the adjacent exons.  Since the right side of exon 15 matches up with the left side of exon 17, removing exon 16 would produce an in-frame transcript.  You can also use the chart to predict the exon skip needed for an exon-deletion mutation.  For instance, if someone has a deletion of exon 52 and you administer an oligo to skip exon 51, the right side of exon 53 fits like a puzzle piece with the left side of exon 50.  That shows that the transcript missing exons 51 (by oligo) and 52 (by mutation) would produce an in-frame dystrophin transcript.

Hello we found out my son has a mutation of Exon 16 also, but our doctor told us that it was not a stop codon and that the entire dystrophin message is out of frame after the insertion. Was hoping PTC 124 would help my son, but with his mutation looks like exon skipping might be better for him.

 

Hi Jon

 

What about stop codon in exon 40 ? Could PRO044 be a canidate ? The right side of exon 40 is the same as the left side of exon 45. Do I read it wrong ?

Hi Berit,

 

Exon 40 is shown with the same shape on each side (it's a rectangle).  That means its number of bases is evenly divisible by three and skipping the exon won't cause a frameshift of downstream sequence.  Likely the most direct approach would be to use an oligo that targets exon 40, causing it to be skipped and eliminating the stop codon it contains from the mature mRNA.  Because downstream sequence would still be in-frame, no additional oligo would be needed.

 

I should point out that I'm a molecular biologist, not a clinician.  So far, this appears to be a reasonable strategy for addressing an exon 40 stop codon.  As exon 40 oligos undergo preclinical evaluation, surprises might emerge.

 

This is a case where accelerated approval of oligos for the the less-common DMD mutations could really help.  We'll need to see one or two oligos approved, after which (finders crossed) with luck, good ethics and perhaps some political input, oligos targeting other exons might have their cost of approval decreased and rate of approval accelerated.

Hi Jon

 

Yes, I am aware that you are a molecular biologist and not a clinician. That's why I asked you :-)) Very helpful information, as always. Thank you.

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