Two mutations on a chromosome

Question

Hello,

My 3 month old son was diagnosed two months ago. He was found a first mutation, W1282X, and the second has just been found.

He has two mutations on a chromosome: the R170H mutation and one that apparently had never appeared before, C243DelT, also diagnosed as a stop mutation (as W1282X).

What about when there are two mutations on a chromosome? Does one take precedence over the other? Do both of them explain the symptoms of the disease? Because it seems that the R170H is a moderate one, I was wondering if it could alleviate symptoms?

Thank you.

Answer

Hello,

There are over 1800 mutations discovered on the CFTR gene (the cystic fibrosis gene), but they are grouped into six classes according to the way they affect the synthesis or functioning of the CFTR protein. Class 1 mutations (including stop mutations) prevent the complete synthesis of the CFTR protein and result in a truncated protein. Your son is carrying on each of his two CFTR genes, a class 1 mutation; he is compound heterozygous W1282X: c.243delT.

The other mutation that he carries, the R170H mutation is a class 4 mutation. When it is the only mutation on a gene, it does not prevent the CFTR protein to reach the cell membrane but alters the chloride secretion through the CFTR channel. Class 4 mutations are generally associated with less severe clinical manifestations than class 1 mutations because a small portion of the protein can be active. In particular, most patients who have at least one class 4 mutation have a pancreas that works well.

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 a part of the clinical expression of cystic fibrosis. However, if two mutations of different classes are on the same gene, it is unlikely that the moderate mutation prevents the severe mutation to be active.

However, it is important to know that the clinical impact of mutations in a given class is extremely variable, particularly in terms of respiratory impairment. It is known that other factors modulate the severity of CFTR genotype, either genetic (modifier genes) or environmental. Thus, patients carrying the same mutations can have a very different disease severity and some patients with two "severe" mutations do not have more severe respiratory disease than patients with "moderate" mutations.

Best regards.
Dr Dominique Hubert

14.05.2012