F508del+R553X

Question

Dear expert team,

my daughter (now 12 weeks old) was diagnosed with CF at 6 weeks. The gene test showed the following mutations: F508del and R553X.

Even though I am aware that progression can vary significantly, I would still like to get some further information on these mutations. I read that F508del usually causes rather severe lung symptoms, whereas R553X is supposed to have a less serious impact but to cause problems with liver function.

Is this information correct? And can we hope that progression will be milder if “only” one serious mutation was found?

Many thanks for your answer!

Answer

Hello,

the F508del mutation is the most common CFTR mutation worldwide and therefore also represents the classic clinical picture of cystic fibrosis (CF). However, it is definitely known today that progression may quite possibly vary significantly, even in patients with identical genotypes, first and foremost among those who are F508del homozygous. Due to the F508del mutation, the majority of the genetic products (chloride channels) do not reach their place of operation (plasma membrane) but are being decomposed early on. A small, non-predictable portion is folded and developed correctly, reaches the plasma membrane, and can fulfil its task as a chloride channel.

The R553X mutation causes a complete functional loss of the chloride channel by not allowing any intact protein to develop.

The F508del/R553X combination is thus generally associated with classic CF and a variation in progression will mainly be determined by the fraction of functioning F508del genetic products that reach the plasma membrane. Furthermore, of course, progression is determined as well by the genetic disposition (genetic background) as a whole and by various environmental influences.

Our own studies with patients who have the F508del/R553X combination have shown that for a majority of the individuals, the lung function up until about 12 years of age is significantly better than in F508del homozygous patients; after that, however, lung disease progressed and was observed to be similar to that of F508del homozygous patients.

It is important to stress, though, that no clear prognosis can be given and that, as mentioned above, progression is not determined by the CFTR genotype alone but by the interaction of several factors and influences.

I hope my answer was helpful to you.

Kind regards,
Prof. Sabina Gallati

03.11.2011