R347P mutation

Question

There was a mistake in my earlier question. My son’s mutation is Delta F 508 / R347P. We would appreciate it if you could provide some information on research findings concerning this. Thank you.

Answer

Dear questioner,

F508del-CFTR refers to the most common CF-causing mutation, in which the F building block (phenylalanine) at the 508th position of the CFTR protein is missing. As a result of the F508del mutation, the CFTR protein in the cell cannot be processed in the regular way: only very small amounts reach the destination, the outer cell wall. Molecular biologists call such dysfunctions “class II mutations.” In turn, this means that F508del can only transport small amounts of chloride. For R347P, the situation is a bit different: this mutation got its name because instead of building block R (arginine), there is a P (proline) inserted instead at position no. 347 of the CFTR protein. This altered CFTR protein does reach the destination in the cell, but it acts only in a limited way there. R347P belongs to the “class IV mutations.” In CFTR geneticist language, like all other class-IV mutations, R347P is a mild mutation whose carriers have a milder progression compared to patients with e.g. two class-II mutations. Pancreatic sufficiency is one such milder variant of cystic fibrosis. Upon observing a group of CF patients with the R347P variant, some authors also find hints to a milder progression of the lung disease. Unfortunately, the observations made in these studies are only of limited use for the individual patient: it is true that it is possible, depending on the inherited mutations, to draw conclusions about the average progression of the disease in a group of patients with the same CFTR mutations; however, the validity for the progression of an individual patient is not always given. A current statement of an international CF expert committee says that “…broad connections between mutation type and development of the disease are only useful for epidemiological research, but the CFTR genotype does not predict the progression of the disease in individuals. It is therefore not recommended to use the CFTR genotype for predictions on the prognosis with CF patients at the time of diagnosis....” (for the sake of completeness, here is the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The reason for this lack of predictability for individual people lies in the sum of all factors that influence the progression of cystic fibrosis apart from the CFTR mutation genotype (environmental factors, other inherited features, particularly important: doctor and therapeutic management of the disease) – according to the current assessment, these “non-CFTR factors” play a bigger role in the progression of the disease than the CFTR genotype alone.

Kind regards,
Dr. Frauke Stanke

22.03.2012