Mutation delta F508 and L227R

Question

Hello my son (3 years) has these two mutations, but I can not find anything on the L227R. Can you tell me more, particularly its class? Do you think the new treatments that are being developed like VX770 will bring something in his case?

Thank you very much

Answer

Dear questioner,
There are over 1800 mutations discovered on the CFTR gene (the cystic fibrosis gene), which 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, however resulting still in a residual expression and function of the ion channel.
When a patient has a mutation of a different class in each of its 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 2 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 distribution of mutations into classes is not always unquestionably and possible.

In the case of your son, one mutation (F508del) belongs to class II, however, the other mutation (L227R) can until now not be classified in a certain mutation class. It is a missense mutation (point mutation in which a single nucleotide is changed). This mutation has been found in 6 patients from the CFTR2 database (includes 40 000 patients). This mutation is still under evaluation. At this time, the CFTR2 team does not have enough information to determine whether or not L227R causes CF.
However, mutation analysis only gives a rough direction but it has clearly to be 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 severity of disease differs substantially even between patients with the exact same mutations. Some patients with two "severe" mutations do not have more severe respiratory disease than patients with "moderate" mutations.
Therefore, it is of high importance that the individual patient is seen regularly in a certified CF center and follows his individual treatment program.
About the value of new treatments: correctors or modulators, the answer can not be given, as functional tests have not been conducted on this mutation.
Sincerely,
Dr. Sophie Ravilly

08.10.2012