[CFTR protein and molecular mechanisms of pulmonary involvement in cystic fibrosis]

Cystic fibrosis is an often fatal hereditary disease mainly affecting the epithelium, especially in the airways, the pancreatic ducts, the sudoriparous glands and bile ducts. The pathophysiologic mechanism is complex but involves abnormal epithelial ion transport which controls water movement through the epithelial layers. In the bronchi, there is deficient secretion of chloride activated by cyclic AMP and exaggerated sodium absorption which contributes to dehydrated bronchial secretion and impaired mucociliary clearance. The cystic fibrosis gene was cloned in 1989. It encodes for a protein called cystic fibrosis transmembrane conductance regulator or CFTR. This protein belongs to a group of proteins which bind ATP and are implicated in ion transportation across membranes. The CFTR protein has several functions and is involved in the cyclic AMP regulation of the chloride channel. More than 500 mutations of the gene encoding for the CFTR protein have been described in cystic fibrosis. The most frequent mutation is a phenylalanine deletion in position 508 or delta F508 which occurs in approximately 70% of the mutations observed in France. Progress in our understanding of the molecular and functional consequences of the different mutations has been rapid, but the correlations between each mutation and the clinical phenotypes observed have not been fruitful. Many advances in the last years using murine models of cystic fibrosis have been developed and clinical trials using genetic therapy are now being conducted.