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The membrane protein, cystic fibrosis transmembrane conductance regulator (CFTR), functions as an ion channel.1 2 It is located primarily in the apical plasma membrane of epithelial cells, where it acts as a ‘gateway’ for chloride ions to leave the cell after a rise in intracellular cAMP. In addition CFTR has a regulatory role over other ion channels in the cell membrane.3 4CFTR is the product of a gene on the long arm of chromosome seven, theCFTR gene.
Cystic fibrosis is an autosomal recessive condition, caused by mutation of both CFTR gene alleles. Over 600 mutations of theCFTR gene have been identified, however one mutation, ΔF508, accounts for the vast majority of cystic fibrosis. Why does this unusual mutation, a codon deletion, have such high prevalence? Greater understanding of the molecular consequences of ΔF508 may answer this question and, more importantly, lead to therapeutic opportunities. This article will review the molecular biology of the ΔF508 mutation with particular reference to clinical implications.
Identification of the CFTR gene
Identification of the ‘cystic fibrosis gene’ was achieved by examining ‘informative families’ (with two or more affected children) for genetic linkage with a large number of genomic probes (short sequences of DNA that match one area of the human genome). This strategy relied on two assumptions; that adjacent genes tend to be inherited together through generations and that one mutation would predominate in this condition. In 1985 linkage of the ‘cystic fibrosis gene’ to markers on chromosome seven was reported.5 6Calculations from the inheritance patterns indicated that two of the markers were relatively close and on either side of the gene. However there was still a lot of chromosomal ground to cover. It was four years until Tsui and his colleagues, using a technique that combined the mundane with the extraordinary (walking …