F508del and 1717-1G greater than A in heterozygous condition

Question

Can you say anything about progression of the mutations mentioned above? I was not able to find any information on F508 in connection with 1717-1G>A.

Our son (6 years old) had intestinal obstruction at birth. Later he had to have nasal polyps removed. He is taking Kreon®/pancreatin 10.000 (ca. 5 capsules per day) and is developing well. His lung function is good too (he has a cough about once a year with antibiotic treatment). He has the typical round fingernails.

Many thanks for your answer.

Answer

Dear questioner,

the answer to your question has two parts:
1. what do the abbreviations F508 (actually F508del) and 1717-1G>A really mean; and
2. in how far is this information significant for your son.

The most important information first:
2. In how far is the information “F508del/1771-1G>A” significant for your son:
All that can be deducted from this is the fact that your son has a typical form of cystic fibrosis (CF) and carries one of the rarer mutation genotypes (F508del twice is much more common). On principle, CF is a multi-organ disease – this means that it affects all organs that develop the CFTR gene which is defective in CF (i.e. the digestive and respiratory tracts). It is indeed right that, depending on the inherited mutations, it is possible to draw conclusions about the average progression of the disease in a group of patients with the same CFTR mutations, but the validity for the individual progression of a single patient (here: your son) is not given. A current statement of an international CF expert group reads as follows: “…broad connections between mutation genotype and development of the disease are helpful for epidemiological research, but the CFTR genotype does not predict the progression of the disease in individual persons. Using the CFTR genotype to predict prognosis in CF patients at the time of diagnosis is therefore not recommended…” (for the sake of completeness, here is the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The cause of this lack of predictive power for the individual lies in all factors that influence progression in CF apart from the CFTR mutation genotype (environmental factors, other inherited features, particularly important: doctor and therapeutic management) – according to the current evaluation, these “non-CFTR factors” have a greater significance for the progression than the CFTR mutation genotype alone.

I am therefore happy to hear that your son is doing very well – this, however, is not owed to the mutation genotype “F508del&/1717-1G>A.” Everything else is more important: access to optimal therapy as well as kudos and support from the family during therapy.

Now, concerning the abbreviations F508 (actually F5089del) and 1717-1G>A:
1. Mutations in the CF-causing CFTR gene follow a nomenclature that is conclusive and comprehensible indeed only to molecular biologists: the CF mutation F508del is called thus because the “F” building block (the “F” stands for the amino acid phenylalanine) is missing at position no. 508 of the CFTR protein (i.e., it is deleted; “del” for short). The numbers refer to the protein building blocks, of which CFTR has 1480 in total. Thus, your son’s missing “F” at position 508 can be found in the first third of the CFTR protein.

1717-1G>A is a bit more complicated to translate: the actual CFTR protein is read from the carrier molecule “mRNA,” which contains more information than is necessary to build the actual protein building blocks. These pieces of information are present in a fragmented way, roughly like this:
informationforCFTRproteinno.1 – connecting piece – informationforCFTRproteinno.2 – connecting piece – informationforCFTRproteinno.3 – connecting piece – informationforCFTRproteinno.4 – connecting piece, etc. There are a total of 27 of such information fragments for the CFTR protein. In order to label something here, one does no longer count the protein building blocks from 1 to 1480, but the building blocks of the carrier molecule “mRNA” from 1 to 4440. In the 1717-1G>a mutation, the mistake lie at the “first-carrier-building-block-before-informationforCFTRproteinno.10” position, i.e. roughly halfway in the CFTR gene. There, a “G” is supposed to be inserted (with “G” signifying guanine, a building block for the mRNA carrier); with your son, there is an “A” at this position instead (short for adenine). Thereby, the beginning of the “informationforCFTRproteinno.10” section cannot be recognized anymore and the rest is read in a completely wrong way. However, as mentioned above, all of this is of interest only for research: access to optimal therapy as well as kudos and support from the family during therapy are much more important than the CFTR mutation genotype!

Kind regards and all the best for your son,
Frauke Stanke

10.11.2011