Cystic Fibrosis: A Defective Membrane Chloride Channel
Posted February 1, 1998
Approximately 30,000 people in the U.S. suffer from cystic fibrosis (CF). This common genetic disorder mainly strikes Caucasians. People who have two recessive genes
for CF experience many kinds of medical problems, including the buildup of excessively thick mucus in their lungs, pancreas, intestines, and liver. In the lungs, this buildup impairs
breathing and provides an excellent growth medium for bacteria.
For 30 years physicians have known that sweat from CF patients was abnormally high in salt content. This led to a diagnostic test for CF called the sweat test, which
measures the salt content of a patient's sweat. But why is the sweat of CF patients so salty? This can be explained by examining the defect that results in this disorder.
People with CF have problems with the way that water and salt ions, especially chloride ions, pass through the plasma membrane of their epithelial cells. In a CF patient's
sweat glands, chloride ions are not reabsorbed into the cells; they are excreted in a person's sweat. When the chloride ions are excreted, this results in fewer chloride ions outside
the cell. Water does not leave the cell because the concentration of chloride ions outside the cell is smaller than the concentration inside the cell. The result is that water does not
diffuse out of the cells, and the mucus secreted is too thick because it is not mixed with water.
People with CF make a defective chloride transporter protein. This protein, named CFTR (cystic fibrosis transmembrane conductance regulator), is found in the plasma
membrane of epithelial cells. This protein is coded for by DNA located in the middle of human chromosome 7. In 70 percent of CF patients, the defect is due to a deletion of three nucleotides
from the CF gene, and the resulting CFTR lacks one amino acid. The malfunction of the CFTR channel prevents chloride movement from the inside of the lung epithelial cells outside the
cells into the lung airways. This defect indirectly causes the cells to take up extra sodium. The mucus in the airways becomes thicker and more resistant to removal. Bacteria flourish
in this environment, leading to lung infection, the main cause of early death in CF patients.
Currently many scientists are studying and testing gene therapy protocols which aim at delivering a normal copy of the CFTR gene to cells. Several research groups
have attempted to deliver the correct CFTR gene into patients using a genetically engineered adenovirus. A major concern was safety to the patient and others. Using this approach scientists
have been able to restore proper chloride channel function temporarily.
References
Welsh, M.J. and A.E. Smith. "Cystic Fibrosis," Scientific American, Vol. 174:12, December 1995, pp. 52-59.
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