The cystic fibrosis transmembrane conductance regulator gene.

Since identification of the gene responsible for cystic fibrosis (CF) in 1989, significant progress has been made in elucidating the mutational basis for this severe, autosomal recessive disease. Such advances have been of major importance in furthering our understanding of the basic defect in CF. Studies of the protein product of the CF gene, referred to as the CF transmembrane conductance regulator (CFTR), indicate that the protein is a Cl- channel but may have additional functions. The most common mutation of the CF gene (delta F508), which leads to the deletion of a single amino acid on the protein molecule, occurs in approximately 70% of CF chromosomes, but the CF Genetic Analysis Consortium has documented over 300 other sequence alterations of the CF gene. In addition to single amino acid deletions, other types of mutations include missense, nonsense (stop codon), frameshift, and splice-junction mutations. Studies of potential correspondences among these different mutational types and predicted functional domains of the CFTR molecule may provide important clues to the physiologic role of normal CFTR and how a defective protein might lead to the CF phenotype. Analyses of genotype-phenotype relationships have shown strong correlations between particular mutations and pancreatic function. However, associations between genotype and severity of CF pulmonary disease are not clear-cut, suggesting that the pulmonary phenotype is strongly influenced by other genetic or environmental factors.