Mutations in the CFTR gene cause Cystic Fibrosis

So one of the questions on our Neurobiology test due today was to see if there were any heritable diseases in humans that are caused by defects in ion channel genes. I discovered that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been linked to Cystic Fibrosis (CF).

CF is a genetic disease that affects the lungs and digestive system of its victims. The defective CFTR gene produces a thick, sticky mucus that provides an environment for life-threatening pathogens to establish an infection, and can clog the lungs. This unusually thick mucus also interferes with the pancreas, and impairs the enzymes that help to break down food and allow the body to absorb it. The symptoms of CF include frequent lung infections; persistent coughing, oftentimes accompanied by phlegm; wheezing or shortness of breath; poor growth or weight gain, despite a healthy diet and appetite; salty tasting skin; and difficulty in bowel movements or greasy, bulky stools. The incidence is about one thousand new cases a year.

This mutation affects the physiology of the affected cells in many different ways. CF patients with pancreatic problems show a reduced ability to transport bicarbonate, which coincides with the evidence that CFTR regulates a chloride-coupled bicarbonate transport. The importance of bicarbonate is that it affects the pH of the cells. Thus, because CF patients have defective CFTR proteins, they secret a more acidic fluid, whereas normal tissues secrete an alkaline fluid. Bicarbonate and pH levels are important because they affect bacterial binding to cells, with the CF condition (more acidic) being more conducive to bacterial binding. This was demonstrated in a study by Choi et al. (2001), from which they concluded that bicarbonate transport was important in the functioning of secretory epithelial cells, and thus has implications for CF.

One interesting proposal is that mutations in the CFTR gene are still prevalent in the human population because the heterozygous condition may convey increased resistance to infectious diseases. In a study by Pier et al. (1998), it was discovered that the bacterium that causes typhoid fever, Salmonella typhi, uses the CFTR protein to enter into epithelial cells. So in CF patients, with defective CFTR proteins, S. typhi is not as able to attach to and invade epithelial cells, and thus less likely to establish an infection.

1. Choi, J. Y.; Muallem, D.; Kiselyov, K.; Lee, M. G.; Thomas, P. J.; Muallem, S. 2001. Aberrant CFTR-dependent HCO(-3) transport in mutations associated with cystic fibrosis. Nature 410: 94-97.

2. Pier, G. B.; Grout, M.; Zaidi, T.; Meluleni, G.; Mueschenborn, S. S.; Banting, G.; Ratcliff, R.; Evans, M. J.; Colledge, W. H. 1998. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393: 79-82.


  1. Val says

    CFTR also seems to regulate expression and function of other ion transporters such as NBC (sodium bicarbonate transporter), NHE (sodium hydrogen exchanger) and others. This speaks to the “regulator” function identified in its name. I don’t have the references in front of me but one is Shumaker et al in AJP cell,1999 I think, stuff out of Manoocher Soleimani’s lab.

  2. Jim Thomerson says

    There was a letter to the editor of Nature around 1985 which said that families with CF were 50% more fertile than similar families with no history of CF, This was in spite of the mortality from CF. The extra 50% were males.

    Also recall a Jared Diamond article on CF. He made the case that a person heterozygous for CF was largely protected from Montezuma’s revenge type diseases, a major killer of young children.

    Sounds like some evolutionary implications here.

  3. HappyPig says

    Be careful with Pier’s data. It’s pretty hit or miss. I’ve talked to a few collaborators of his who have expressed concern that the cells he uses (and sends out) have constant mycoplasma contaminations and so throw out some interesting results.

  4. Loren Petrich says

    I’ve seen a theory that the gene variant that causes Cystic Fibrosis is useful when alongside a “normal” version of that gene, because it helps protect against cholera and other diarrheal diseases.

    The diarrhea from such diseases is from the disease microbes causing the cell-membrane chloride pumps to become more active, thus pumping more water out of the cells, and thus causing dehydration and sometimes death. This is convenient for the microbes, however, because they can then spread more easily.

    However, the CF mutation makes such pumps less active, and thus less vulnerable to this microbe-induced overactivity, though at the price of causing the CF symptoms when both CF-versions are present.

    Thus, it is something like sickle-cell anemia and similar genetic diseases being caused by being homozygous in various genes’ alleles that protect against malaria; there is a speculation that Tay-Sachs disease is caused by something that protects against tuberculosis in a similar fashion.

  5. Austin says

    Having CF (woo hoo! Delta F508 gene mutation, the most common variant), I’m pretty familiar with all this stuff. I’ve also read that having a heterozygous mutation helps protect against cholera, and thought it was a pretty interesting theory. But while this would help explain why such a harmful mutation could stick around humanity’s gene pool for so long, it doesn’t offer any answers as to why the disease is almost entirely restricted to caucasians. I’m curious to see what further research comes up with.

    Re: #3, I’m assuming the term “CF families” refers to families where one or more of the children have CF; parents with CF have always been pretty unusual (though increasingly less so) due to the early mortality and widespread infertility the disease causes.

    sailor, thanks for the link to Orac’s article; somehow I’d missed that one. Interesting stuff.

  6. Loren Petrich says

    Something that could well make a difference is living in big cities, where diarrheal diseases can easily spread in the absence of good sanitation. But though that can explain why white people get CF, there is nevertheless the question of southern and eastern Asians, who have also had big cities for a long time.

    Living in cities may also be a factor in Tay-Sachs disease, at least according to the tuberculosis theory of its presence. Eastern European Jews were often stuck in city ghettos, where tuberculosis could easily spread; according to that theory, this induced the Tay-Sachs counter-adaptation, which has been common in Eastern European Jews.

  7. BrucH says

    Loren, living in big cities may be a factor, but it is far from the only factor, or even a major factor. This is purely anecdotal, of course, but one of my good friends suffers from CF. He is currently (so he says) the oldest known CF patient, well into his forties. He also lives near downtown Houston.

    With good medical treatment and careful attention, he hopes to live for many years to come.

  8. BrucH says

    Hmm… seems I misread your comment. In any case, Houston is not known for excessive cases of diarrhoeal disease, as public sanitation here is quite good. There is an air pollution problem though, which makes it hard on CF patients.

  9. Jim Thomerson says

    I looked it up one time, and, as I recall, CF was first recognized in 1938. My guess was that it had been increasing in frequency as a result of CF increasing simple Darwinian fitness, and, in 1938 became common enough to be noticed. A microbiological colleague pointed out that was about the time of the sulfa drugs, which were the first really efective antibiotics. So CF sufferers could be kept alive long enough for the condition to be diagnosed.

    That CF is, at the moment, a caucasian condition, suggests that the mutation is fairly rare. Clearly outbreeding will transfer the mutation to other human groups over time.