G551D/G542X

Question

My husband is suffering from CF and carries the mutations G551D/G542X.
Do theses mutations express themselves within the cells or does one mutation dominate the other ?

Answer

Dear Madam,

G542X and G551D are both CF-causing mutations, that means they are causing a clinical illness. (CF-causing in opposition to other mutations or variants of the CFTR gene of which the clinical expression is not yet known and/or which may have no clinical expression).

G542X is a class 1 mutation and therefore there is no expression of the CFTR protein on the surface of the cell membrane. G551D is a class 3 mutation, so there is a defect in the regulation of the CFTR protein; even if the protein is expressed on the cellular surface it does not correctly fulfill its function as an ion channel.

At present, we have access to data bases in which the clinical effects of these mutations are described for a significant numbers of patients. However, in general the clinical expression of a mutation is described in combination with the ΔF508 mutation. In this case, the two mutations you mention induce a classical clinical picture with a positive sweat test and an exocrine pancreatic insufficiency in the majority of patients. As you probably know, there is no a close relation between the type of mutation and the degree of lung disease because the pulmonary involvement seems to depend not only on genetics, but also on environmental factors. Thus, classical CF is seen if either one of the two mutations you mention is combined with the ΔF508 mutation. We do not know today what happens when these two mutations are found in the same person (too little cases are reported) and it is not known if one could dominate the other.

I suppose that your question also concerns the new treatments which are being developped to rescue the transcription of the CFTR protein in case of the G542X mutation and to activate the CFTR protein in case of the G551D mutation. The most advanced clinical development is the drug named ivacaftor (also VX-770; commercial name: Kalydeco®), which activates the CFTR protein in the case of the G551D mutation. The phase 3 clinical study, called STRIVE, included 161 patients and has shown a significant clinical improvement for patients, who were carrying the G551D mutation, when treated with the active product as compared to a placebo. The patients' initial FEV1 was around 60%. Patients receiving ivacaftor showed a 10% improvement of their respiratory function in comparison with control patients over 24 weeks of treatment; they also had less pulmonary exacerbations, and furthermore, they gained weight. These results are promising, but we have to remain careful. For example, the security and the efficacy of the drug over a longer period of time and/or for patients with a more severe respiratory damage will still have to be established. The clinical study of a drug permitting a transcription of the CFTR gene in case of the G542X mutation and therefore an expression of the CFTR protein on the cellular surface is underway (PTC124, ataluren). As for the possibility to combine the two drugs in one and the same patient, it is to soon to say anything; this would be speculative.

In conclusion, I cannot at present give very formal advice as far as your husband, who carries a rare combination of mutations, is concerned. However, the actual pharmaceutical developments are very promising indeed.

Sincerely yours,
Christiane Knoop

14.11.2012

14.11.12
The first results of the Ataluren study can be read under the question "results regarding Ataluren project": ecorn-cf.eu/index.php?id=65&L=0&tx_expertadvice_pi1[showitem]=1999&tx_expertadvice_pi1[search]=Results%20regarding%20Ataluren%20project

D. d'Alquen