Bug in the Box. PTCs in Splicing mutations


A complication is that some CFTR splicing mutations such as
2789+5G->A, 3849+10kbC->T, 621+1G>T, have a modification (Intron
inclusion or exon skipping) that, altering the frame-reading, creates a
PTC (premature termination codon).
In simple words these splicing mutations produce a stop signal
(Codons: UGA, UAA, UAG), that halts the ribosomes during their
translation job.
However, these last years have seen a growing interest around CFTR modulators
(specifically correctors of stop mutations). Indeed some CFTR
modulator studies have reached phase III clinical trial stage (Ataluren).
These correctors are able to skip a stop codon for mutations producing
just a truncated protein (final X mutations, class I). In a phase II
study of the PTC124 molecule, one patient with 3849+10kbC->T was also
included (E. Kerem, 2008).
While not conclusive, this at least suggests that such splicing
mutations could be a target for CFTR correctors.
Then the important question is if the rescued portion of CFTR
(synthesized thanks to the corrector by skipping the stop codon) would
be functional or not. And then if could be a target for potentiators.
That is: Can a combination of Corrector / Potentiator improve the
conditions of CFTR subjects with splicing mutations?

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