Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs), and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs).
Highlights
Cystic fibrosis (CF) is a lethal autosomal recessive disorder in which abnormal regulation of epithelial Cl- channels is associated with the pathophysiology of the disease [1,2]
The cloning and subsequent studies of the CF gene have shown that its product is a low conductance, c-AMP-regulated chloride channel with properties distinct from those of other Cl- channels expressed in epithelial cell membranes [1,5,6]
The original hypothesis that CFTR would function as a conductance regulator seems to be correct, as several ion transport abnormalities found in cystic fibrosis airway epithelial cells cannot be explained by mutations in the CFTR chloride channel
Summary
Cystic fibrosis (CF) is a lethal autosomal recessive disorder in which abnormal regulation of epithelial Cl- channels is associated with the pathophysiology of the disease [1,2]. The major causes of morbidity and mortality in CF patients are opportunistic chronic lung infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. The cloning and subsequent studies of the CF gene have shown that its product is a low conductance, c-AMP-regulated chloride channel with properties distinct from those of other Cl- channels expressed in epithelial cell membranes [1,5,6]. Mutations in the CFTR gene reduce Clpermeability in several affected exocrine epithelial cells This defect has attracted attention to the chloride transport function of CFTR and to the other Cl- channels that may TMD1. The importance of each CFTR domain in the chloride channel and conductance regulator functions of the protein as well as the influence of the most common mutations in CF will be discussed in this review
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