R1166C and 2142delT

Question

Hello,
what is the clinical course of the illness with the above mentioned mutations? Are any new drugs for those mutations available?

Answer

Dear questioner,
I answer in two parts: 1. about the clinical course and 2. about the new medications

1. Course of the illness of CF with the mutation genotype R1066C/2143delT
In case of R1066C and 2143delT it deals with "typical" CF mutations, that are accompanied by an increased salt concentration in the sweat, loss of pancreatic function and impairment of the gastro-intestinal system as well as the airway system. A detailed prognosis cannot be made according to the mutations, as the influence of non-inherited factors on the course of the illness in CF is great: the pyhsician (the best a physician with experience in CF), the therapy and the circumstances, under that the partly very time-consuming therapeutical aims are converted, have a marked influence on the e.g. conservation of the lung function. I hope therefore, that your daughter is already regularly seen in a CF center.

2. To the therapies with new medications like Ivacaftor, Lumacaftor and Ataluren:
R1066C is a so-called reading-mistake mutation, which has instead of the building block "R" (in the functioning CF-protein) at the position 1066 the building block "C" (defective CF-protein). Vertex has with VX-770, VX-809 and VX-661 three drugs in development, that act on different reading-mistake mutations. Actually, R1066C is in contrast to other reading-mistake mutations like G551D not included in studies with these drugs. R1066C is not a candidate for Ataluren (this is acting on most of the stop mutations, they are called building-block position X, the X stands for the end of the protein).
2143delT however, is a frameshift mutation, that integrates such an early stop codon: 2143delT means in translation, that at the position 2143, the building block T is missing. This is this time, for confusion, the numeration of the building block of the nucleic acid messenger, from which emerges in a second step the CF protein. In the frame of this translation, from 2143delT the shortened CF protein L671X is generated, where at the position 671 not a building block "L" (in the functioning CF protein) is found, but the signal for the "end of the protein" (X). If Ataluren represents a therapy for 2143delT (or with another name L671X), is to my knowlegde not clarified.

In summary:
For a good prognosis the therapy at a qualified CF Center is of utmost importance - also for the mutations R1066C and 2143delT. Mutation-specific drugs are at the moment probably available for 2143delT, if R1066C will be able to be treated in the future with newly developed drugs, is at the moment unknown.

Best regards,
Frauke Stanke

06.06.2015