ΔF508/R553X

Question

Dear expert team,

Could you please help me understand a paper that I found about the above mentioned genotype which is the genotype of my 7-month old daughter.

The article "Early Detection of Lung Disease and Its Association with the Nutritional Status, Genetic Background and Life Events in Patients with Cystic Fibrosis" (von Richard Kraemer, Christoph Aebi, Carmen Casaulta Aebischer, Sabina Gallati; Department of Pediatrics, University of Berne, Berne, Switzerland; Respiration 2000;67:477-490 (DOI: 10.1159/000067458)) says the following:
"R553X seems to decrease the influence of the ΔF508 deletion in ΔF508/R553X compound heterozygotes, causing a milder course and slower progression."

I do not understand how a class-1-mutation (where there is no CFTR synthesis at all according to my understanding) can attenuate a class-2-mutation where "only" the CFTR maturation is malfunctioning?
I am a medical lay person but I would like to understand the processes which are influencing the course of the disease.

Best regards,
KS

Answer

Dear questioner,

The paper you mentioned is older than 10 years. The information given referred to the state of knowledge at that time and is now outdated.
But we do still notice in our patients with the combination F508del/R553X that frequently in childhood the course of the disease regarding the lung disease is a bit better than in the F508del-homozygous ones. In adolescents, however, they are getting worse so that there is no difference between them and the F508del-homozygous ones anymore. Both genotypes show a better course than patients who carry a F508del- and a 3905insT-mutation.

The explanations for these observations are currently matter of various functional studies. One of our research projects is dealing with the question if transcripts of the R553X-mutation are always broken down or if part of it actually is translated into proteins and, if this is the case, if all produced proteins are truncated and as a result are broken down or if from time to time the early stop codon is skipped and a functioning protein is being produced. If all transcripts of the R553X-allele are broken down, the course (apart from all other influencing factors) is determined by the remaining rest function of the F508del-allele varying from patient to patient. But as said before, these explanations for the observed average clinical course of this genotype are based on hypotheses that have to be proven or disproven by complex studies.

I hope to have been helpful with this information.

Best regards,
Prof. Dr. Sabina Gallati

17.04.2012