Cause of CF

Question

What is the cause of CF on a molecular level?

Answer

Thank you for this interesting question. This is a very complex question. Therefore we will give you a global picture.

CF is caused by a mutation (an error) in the CFTR gene (hereditary material that contains all information to make the CFTR protein) so that the production of correct CFTR goes wrong. Only if all steps in the production process happen normally a complete and well functioning CFTR protein will be present at the surface of the cell where it can take on it’s normal function. You can read a lot about the function of CFTR protein in the sections on genetics. In a nutshell the CFTR protein functions as a salt channel in the lining of the airway as well as in other organs. If, in the airway, it functions insufficiently or if it is absent, too little chloride goes to the outside and an excess amount of sodium is taken up into the cell. The net result will be less water towards the outside so that the lining of the airway will be too dry. This leads to lots of thick sticky secretions in the airways.

More than 1600 different errors in the CFTR genes have been discovered. Knowing exactly what consequence an individual mutation has for the production and function of the protein is a next level of understanding. Every error can have a different effect on the production of normal CFTR protein but for practical purposes mutations are grouped in mutation classes. (read more about this in the section on genetics).

Lastly understanding every part of the large CFTR protein is important because mutations have been discovered in the entire length of the gene. The CFTR channel has different domains that need to be activated according to a fixed pattern to make sure the channel is opened (active form). When there are changes in the transmembrane part (the part that fixes the channel into the cell membrane) the activity of the channel can be lower for instance because the charge of the channel is changed. Changing one compound to a more negatively loaded compound can diminish the function of the channel because the chloride that needs to travel through the channel is also negatively charged.

The CFTR channel is not active or opened the whole time. How exactly the channel opens and closes is another level of understanding. The speed with which the channel opens can be disturbed or the duration during which the channel remains open can be disturbed. Very detailed studies evaluate the structure of the whole channel and also the opening and closing mechanism. For every mutation it can thus be examined how the structure and the function changes. The CFTR protein influences other proteins in its neighborhood and also this cooperation between different proteins is being studied. Knowing the function of the normal CFTR protein up to its last detail can help in the discovery of new medicines or strategies to correct the CFTR function. We hope this answer helps.
Prof. Dr. K. De Boeck

11.02.2010