Mutation 394delTT and R1162X

Question

Dear expert team,
My son was diagnosed with the above mutations. Could you explain to me the meaning and scope of this mutation and provide some general information on it?

Many thanks!

Answer

Dear questioner,

Concerning your first question – the meaning of R1162X and 394delTT: Mutations in the CF-causing CFTR gene follow a nomenclature that is conclusive and comprehensible indeed only to molecular biologists. The CF mutation R1162X got its name because there is a stop codon (abbreviated X) instead of the building block “R” (the R stands for the amino acid arginine) sitting at position no. 1162 of the CFTR protein. This means that, after 1162 building blocks, the cell gets a signal from this mutated CFTR gene to stop protein synthesis and only this shortened CFTR protein is brought forth. The actual CFTR protein is read by the “mRNA” messenger molecule. With the 394delTT mutation, the number signifies a building block on the messenger RNA level: 394delTT means that the messenger RNA for CFTR is missing two Ts (for thymidine) at position no. 394 – since unfortunately amino acids are always characterized by three building blocks on the DNA level, this mutated CFTR gene only produces unreadable gibberish for the cell. To sum it up: R1162X – shortened CFTR protein; 394delTT – no usable information. Both are so-called classic CF mutations, which means they lead to CF.

Concerning your second question – general information on these mutations: It is indeed correct that, depending on the inherited mutations, it is possible to draw conclusions about the average course of the disease in a patient group with the same CFTR mutations; however, this does not apply to an individual patient’s course. A current statement of an international CF expert panel says: “Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcoume. The use of CFTR genotpye for predition of prognosis in people with CF at the time of their diagnosis is not recommended. ” (For the sake of completeness, here is the source: Journal of Cystic Fibrosis 7(3):179-196; 2008.) The reason why this is the case lies in all the parameters that influence the course of CF apart from the CFTR mutation type (environmental factors, other inherited characteristics, particularly important: doctor and therapeutic management of the disease) – according to the current assessment, these “non-CFTR factors” bear a much greater significance for the course of the disease than the pure CFTR mutation genotype.

Kind regards
Frauke Stanke

09.10.2012