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.