Leila Cruikshank

What Causes Cystic Fibrosis....More Information On Genetics

The video below provides an in-depth review of the science regarding the CFTR (cystic fibrosis transmembrane regulator) protein.

The CF gene was first discovered in 1989 by a team of investigators at the Hospital for Sick Children. It took a further 2 years for scientists to discover exactly what the CF gene is for. The CF gene contains the instructions on how to build a channel that sits in the membrane of some cells in the body. This channel is a protein and is called CFTR (cystic fibrosis transmembrane regulator) and it functions as a pore that chloride (salt) can move through. CFTR also influences other channels and is important in the movement of sodium in lung airway cells.

Mutations in the CF gene are mistakes in the DNA code that cause dysfunction in CFTR (so that the salt channel does not work properly). During the time that the CF gene was discovered, about 10 different mutations were described. We now know that there are more than 1400 mutations in the CF gene that can cause cystic fibrosis. Some of these mistakes can be more severe than others. If you were reading instructions and there was an entire page missing, that would be a severe mistake and it would be difficult to follow the instructions. However if the mistake was a misspelled word, you could still probably follow the instructions and this would be a mild mistake. In this way, some of the 1400 mutations are severe and some are mild.

The most common mutation causing CF is delta F508 - a deletion of an amino acid called phenylalanine at position 508 in the gene. This results in the CFTR salt channel not being able to fold into the proper shape. The body recognizes this abnormality and breaks down the protein after it is made so that the protein does not move to its correct position in the cell membrane. Thus the delta F508 mutation is a severe mutation. About 65-70% of all CF mutations seen are the F508 mutation and half of the people with CF in our clinic carry 2 copies of this mutation.

Scientists have divided the 1400 different mutations in the CF gene into categories based on their impact on the CFTR protein.

Classes of Mutations

Type I mutations are so severe that no normal CFTR protein is made at all. An example of Type 1 mutations are stop mutations. Normally, the DNA contains instructions to say when the CFTR protein is complete. If there is a stop mutation, it is as if the last few pages of the instructions are missing so you are left with a CFTR protein that is only partially completed and thus does not work as a salt channel. The more common of these mutations are the G542X and W1282X mutations.

Type II mutations are mistakes that cause a problem with processing the CFTR protein. The CFTR protein is not made correctly so the body breaks down the protein before it can reach the cell surface. Delta F508 is the most common Type 2 mutation. Type 2 mutations are considered severe mutations.

Type III mutations are mistakes that mean that, although the salt channel is made correctly and gets to the correct position in the membrane of the cell, it does not work. The G551D mutation is an example of a Type 3 mutation and Type 3 mutations are also severe mutations.

Type IV mutations are considered mild mutations because the the CFTR protein is in the correct location on the cell membrane and it does work to move salt but it doesn't function properly. This is also called a conductance problem. The R117H mutation is the most common Type 4 mutation.

Finally, Type V mutations are also mild mutations where the number of salt channels is reduced but each individual channel functions normally. These are very rare mutations and include 3849+10kbC->T and A455E.