CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (66–70%) of CF cases worldwide and 90% of cases in the United States; however, there are over 1500 other mutations that can produce CF. Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.
The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long. More specifically the location is between base pair 117,120,016 to 117,308,718 on the long arm of chromosome 7, region 3, band 1, sub-band 2, represented as 7q31.2. Structurally, CFTR is a type of gene known as an ABC gene. The product of this gene (the CFTR) is a chloride ion channel important in creating sweat, digestive juices and mucus. This protein possesses two ATP-hydrolyzing domains, which allows the protein to use energy in the form of ATP. It also contains two domains comprising 6 alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.
In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.
Read more about this topic: Cystic Fibrosis