ΔF508 (delta-F508, full name CFTRΔF508 or F508del-CFTR; rs113993960) is a specific mutation within the gene for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation is a deletion of three nucleotides spanning positions 507 and 508 of the CFTR gene on chromosome 7, which ultimately results in the loss of a single codon for the amino acid phenylalanine (F). A person with the CFTRΔF508 mutation will produce an abnormal CFTR protein that lacks this phenylalanine residue and which cannot fold properly. This protein does not escape the endoplasmic reticulum for further processing. Having two copies of this mutation (one inherited from each parent) is by far the most common cause of cystic fibrosis (CF), responsible for nearly two-thirds of cases worldwide.
The CFTR gene is located on the long arm of chromosome 7, at position q31.2, and ultimately codes for a sequence of 1,480 amino acids. Normally, the three DNA base pairs A-T-C (paired with T-A-G on the opposite strand) at the gene's 507th position form the template for the mRNA codon A-U-C for isoleucine, while the three DNA base pairs T-T-T (paired with A-A-A) at the adjacent 508th position form the template for the codon U-U-U for phenylalanine. The ΔF508 mutation is a deletion of the C-G pair from position 507 along with the first two T-A pairs from position 508, leaving the DNA sequence A-T-T (paired with T-A-A) at position 507, which is transcribed into the mRNA codon A-U-U. Since A-U-U also codes for isoleucine, position 507's amino acid does not change, and the mutation's net effect is equivalent to a deletion ("Δ") of the sequence resulting in the codon for phenylalanine at position 508.
ΔF508 is a class II CFTR mutation. The CFTR protein is largely expressed in cells of the pancreas, intestinal and respiratory epithelia, and all exocrine glands. When properly folded, it is shuttled to the cell membrane, where it becomes a transmembrane protein responsible for opening channels which release chloride ions out of cells; it also simultaneously inhibits the uptake of sodium ions by another channel protein. Both of these functions help to maintain an ion gradient that causes osmosis to draw water out of the cells. The ΔF508 mutation leads to the misfolding of CFTR and its eventual degradation in the ER. In organisms with two complements of the mutation, the protein is entirely absent from the cell membrane, and these critical ion transport functions are not performed.
ΔF508 is present on at least one copy of chromosome 7 in approximately one in 30 Caucasians. Presence of the mutation on both copies causes the autosomal recessive disease cystic fibrosis. Scientists have estimated that the original mutation occurred over 52,000 years ago in Northern Europe. One hypothesis as to why the otherwise detrimental mutation has been maintained by natural selection is that a single copy may present a positive effect by reducing water loss during cholera, though the introduction of pathogenic Vibrio cholerae into Europe did not occur until the late 18th century. Another theory posits that CF carriers (heterozygotes for ΔF508) are more resistant to typhoid fever, since CFTR has been shown to act as a receptor for Salmonella typhi bacteria to enter intestinal epithelial cells.
Being a heterozygous carrier (having a single copy of ΔF508) results in decreased water loss during diarrhea because malfunctioning or absent CFTR proteins cannot maintain stable ion gradients across cell membranes. Typically there is a build-up of both Cl− and Na+ ions inside affected cells, creating a hypotonic solution outside the cells and causing water to diffuse into the cells by osmosis.
Several studies indicate that heterozygous carriers are at increased risk for various symptoms. For example:
- It has been shown that heterozygosity for cystic fibrosis is associated with increased airway reactivity, and heterozygotes may be at risk for poor pulmonary function. Heterozygotes with wheeze have been shown to be at higher risk for poor pulmonary function or development and progression of chronic obstructive lung disease. One gene for cystic fibrosis is sufficient to produce mild lung abnormalities even in the absence of infection.
- Cystic fibrosis ΔF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than non-carriers.
- Carriers of a single CF mutation have a higher prevalence of chronic rhinosinusitis than the general population. Because this study examined a general population of CF carriers, some subjects did not possess the ΔF508 variant.
Having a homozygous pair of genes with the ΔF508 mutation prevents the CFTR protein from assuming its normal position in the cell membrane. This causes increased water retention in cells, corresponding dehydration of the extracellular space, and an associated cascade of effects on various parts of the body, including:
- Thicker mucous membranes in the epithelia of afflicted organs
- Obstruction of narrow respiratory airways as a result of thicker mucous and inhibition of the free movement of mucocilia
- Congenital Bilateral Absence of the Vas Deferens (CBAVD) due to increased mucous thickness during fetal development
- Pancreatic insufficiency due to blockage of the pancreatic duct with mucous
- Increased risk of respiratory infection due to build-up of thick, nutrient-rich mucous where bacteria thrive
This collection of symptoms is called cystic fibrosis; however, ΔF508 is not the only mutation that causes CF.
Heterozygous carriers with other mutations
Approximately 70% of cystic fibrosis cases in Europe are due to homozygous ΔF508 mutations (this varies widely by region). The remaining cases are caused by over 1500 other mutations, including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or even a single copy of ΔF508, may cause CF symptoms. The genotype is not strongly correlated with severity of the CF, though specific symptoms have been linked to certain mutations.
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