PTC 124 / Vertex VX-809

Question

My son has the following mutations:

1717 1g --> A (class I mutation) as well as s549R (class II mutation).

“1717 1g --> a” is a class I mutation. More precisely, it is a splice site mutation which, however, triggers a stop codon. Is PTC 124 effective with this kind of mutation?

The other one is a rather rare class II mutation. Provided that a pharmacological drug for the d508 mutation will be developed in the future (e.g., VX-809), could this drug be effective with the S549R mutation as well?

Answer

You probably mean the 1717-1G>A mutation? This is indeed a class I mutation. PTC 124 is effective with class I mutations, though not with all of them, but apparently only with so-called nonsense mutations; i.e., mutations where a premature stop codon is generated through a single nucleotide exchange in the coding sequence. In these cases, PTC 124 prevents the premature stop codon to be skipped, which means that a “fake” amino acid is built into this spot of the CFTR protein; all previous and following amino acids are correct. The CFTR protein with the one “fake” amino acid is functional. With the 1717-1G>A mutation, the RNA is spliced incorrectly. This results in a completely changed sequence of amino acids. The skipping of premature stop codons would not help at all in this case.

In my opinion, whether S549R is a class II mutation or a class III one after all has not been proven. Irrespective of that: the Vertex VX-809 approach is targeted at the correction of the faulty protein maturation/folding in patients with the F508del mutation. To my knowledge, it is completely unclear whether this approach could be effective with other class II mutations as well (F508del is a class II mutation).

Kind regards
Prof. M. Stuhrmann-Spangenberg

24.03.2009