Mutations

Question

Could you give me some information about these 2 mutations, G551D associated with Q1476X : which class do they belong to, which respiratory or digestive problems can they cause, severity of the disease, even knowing that the disease is not similar between subjects. Thank you in advance for your response.

Answer

Hello,
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 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, the mutation G551D is a class III mutation. However, the situation for the Q1476X is not as clear. In general, mutations ending with an X are called “nonsense” or “stop” mutations and most of them belong to class I leading to no functional protein. With Q1476X, however, it is different, as the “stop” is at a site of the gene that is not as important for the production of the protein. The first patient described 1999 from Tunisia with this mutations and delF508 on the other chromosome had only fertility problems, no lung involvement and pancreatic sufficiency. There are 2 patients reported with this mutation in the French registry, with a similar mild phenotype. So it seems that Q1476X together with a CF-causing mutation on the other chromosome, leads to a mild form of CF or even only to a so-called “CFTR-related disorder”.
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. 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 particular, patients over 6 years carrying at least one G551D mutation can now benefit from a new treatment, Ivacaftor (marketed under the name Kalydeco ®). This is a potentiator which activates the ion channel of the CFTR protein in the cell membrane. Clinical studies over 48 weeks showed a response to treatment (versus placebo) with a gain of respiratory function (FEV1 increased an average of 10%), a decrease in respiratory exacerbations, an increase in weight gain (average 3 kg) and improved patient’s respiratory well-being. This treatment consists of tablets (one in the morning and one in the evening) and is generally well tolerated. You can request more information from your CF doctor.
Yours sincerely,
Dr Dominique Hubert

22.11.2012