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CF mutations

I am a mother to a girl with F508del/CFTRdele2,3 (21kb) mutations. She was diagnosed at 2 months old. Now she is 5 and doing very well. Only 2 lung infections, no P.a cultured. Still I am concerned as I read both of the mutations are clasified as "severe". Does it mean that the progress of the desease may be faster, harder? Can you tell how sensitive is she to culture CF bacteria (like P.a.)? Thank you in advance.
Dear questioner,
There are over 1800 known mutations of the CFTR gene (the cystic fibrosis gene) that are grouped into six classes according to the way they affect the synthesis or functioning of the CFTR protein which serves as an ion channel in the cell membrane. Class I-III mutations result in defective synthesis, processing, maturation and regulation of the CFTR protein with an abolished function of the ion channel. Class IV-VI mutations result in defective conductance, reduced function/synthesis and increased degradation of the CFTR protein, though still with a residual expression and function of the ion channel.
When a patient has a mutation of a different class in each of his/her two CFTR genes, the less severe mutation affects the functioning of the protein and therefore part of the clinical expression of cystic fibrosis. In general, patients with two mutations from class I-III exhibit a phenotype associated with pancreatic insufficiency and a more severe course of the disease compared to patients with at least one class IV-VI mutation. Class IV-VI mutations are usually associated with pancreatic sufficiency and milder lung disease. However, the classification of mutations is not always conclusive and possible.
In your case, both mutations belong to class I-III. F508del is the most frequent mutation found in CF patients, in the produced protein one amino acid is missing, so that it is not folded correctly and destroyed too early. CFTRdele2,3 (21kb) is a mutation with loss of parts of the genetic material, therefore the resulting CFTR protein would thus be strongly shortened and therefore inoperable.
However, mutation analysis only gives a rough direction but it has to be clearly stated that the individual clinical course and especially the degree of lung involvement cannot be predicted according to the genotype, as many other genetic (modifier genes, etc.) and environmental factors play a role and the severity of disease differs substantially even between patients with the exact same mutations. Therefore, it is very important that the individual patient is seen regularly in a certified CF center and follows his individual treatment program in order to influence the course of the illness favorably.
Concerning the sensitivity to Pseudomonas aeruginosa, it is of course not possible to make an individual prediction if and when a patient will get colonized with Pseudomonas aeruginosa. Data from patient registries reveal that about 30% in the age group of 2-5 years and about 80% of the age group of 26-30 years are infected with P. aeruginosa. However, early treatment of the first finding of P.aeruginosa with successful eradication in about 80% could reduce the number of P.a. positive CF children and delay a chronic colonization with that germ.
Yours sincerely,
Dr. Daniela d’Alquen (Coordinator of the Central Englishf Archive of ECORN-CF)
Castellani et al in the Journal of Cystic Fibrosis 7 (2008) 179-196: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice"