Function of correctors for stop mutations

Question

Dear ladies and gentlemen,
I would like to know, how exactly the correctors (e.g. Lumacaftor) are acting on stop mutations on the molecular genetic level.
Are those synthetic tRNAs that bind to the wrong stop codons?
I would be pleased if you could explain the function of the corrector molecule to me.
Many thanks and best regards.

Answer

Dear questioner,
in advance: Lumacaftor has NOT been developed for the treatment of stop mutations - the most known substance for the targeted therapy of stop mutations is Ataluren!
In case of the so-called mutation-specific drugs, in general potentiators (Ivacaftor) are distinguished from correctors (Lumacaftor) for CFTR mutations.
Potentiators can enhance the activity for the mutated CFTR, if this reaches the place of action in the cell-membrane (this is the cell-membrane that is orientated to the outside of a polar differentiated epithel cell, that can e.g. be found on the surface of gut mucosa or lung mucosa). Example: G551D-CFTR (NO stop mutation).
Correctors are acting on the maturation way of the CFTR protein in the cell - therefore are resposible that more mutant CFTR reaches the apical cell-membrane. Example: F508del-CFTR (NO stop mutation).

For further information on the acting way of Lumacaftor/Ivacaftor you can use the following link [in Germn]:
muko.info/mukoviszidose-institut/detailansicht/article/mutationsspezifische-therapie-wirkstoffkombinationen-koennen-sich-gegenseitig-behindern/1107.html?tx_ttnews[pS]=1406832566


Ataluren on the other side, is used for CFTR stop mutations. It is acting on the interaction between ribosomes and mRNA and makes an overreading of a premature stop codon possible, therefore a reading inaccuracy.
Best regards,
Frauke Stanke

16.04.2016