Cystic Fibrosis: How do CFTR mutations cause cystic fibrosis?

Two major discoveries have transformed our understanding of cystic fibrosis, a genetic disease in which thick secretions accumulate in airways, digestive organs and sperm duct. The first was that cystic fibrosis involves a basic defect in epithelial ion transport [1], which is manifested primarily as the loss of chloride conductance [2]. The connection between the loss of epithelial chloride conductance and many of the symptoms of cystic fibrosis is explained by a well-established model in which fluid secretion is driven by chloride secretion, the last step of which occurs through a chloride channel [3]. Loss of conductance through the chloride channel reduces fluid secretion, leading to airway obstruction by condensed macromolecules; salt absorption is also compromised in some tissues. The other great advance was the cloning of the cystic fibrosis gene [4], which brought the enormous power of molecular biology to cystic fibrosis researchers. This led to the demonstration that the cystic fibrosis gene product is a chloride channel [5], validating earlier electrophysiological analyses and leading to the hypothesis that the fundamental physiological defect in cystic fibrosis is loss of the chloride conductance mediated by the cystic fibrosis gene product (Fig. 1).