Class I (stop) as the next residual mutations




Can Class I Stop Codon Mutations be treated as another form of residual CFTR mutation after a pharmacologically induced read-through ?

Class I stop mutations have a particular modification in their genotype producing a Stop codon (UGA AUG UAA) . This codon halts the ribosome in the process of translating the mRNA to produce a complete CFTR protein. Suddenly after that this happens, the truncated protein is seen as “trash” and eliminated.
We already discussed about this theme previosuly, related to Aberrant forms of splicing mutations Click Here.

Recently many scientists focused their research on finding modulators correcting this defect and inducing a readthrough, helping the ribosome to skip the halt signal.
The most advanced modulator is PTC124 from PTC Therapeutics ® (ptcbio.com) currently in phase III clinical trial.




New strategies with much more efficient modulators, demonstrated in vitro rescue of as much as 12% of Wild Type CFTR protein ISc Activity in heterozygous patients carrying DF508 and G542X alleles. [Abstract 194 NACFC 2012]

A 12% recovery of WT-CFTR can really improve a CF phenotype, (potentially) This image shows that some WT-CFTR, in a CF cell with a stop mutation (G542X ,R1162X, etc), can be rescued with more than one corrector.
reducing risks related to the pathology and the chronic decline in lung function.
Moreover the recovered protein could also be subject to potentiation, as we can see in this slide below.



*Note that the rescued-CFTR activity can be further potentiated with Vx-770, a CFTR potentiator.



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