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 the three nucleotides that comprise the codon for phenylalanine (F) at position 508. A person with the CFTRΔF508 mutation will produce an abnormal CFTR protein that lacks this phenylalanine residue. This protein does not escape the endoplasmic reticulum for further processing. Having two copies of this class 2[clarification needed] mutation (one inherited from each parent) is the leading cause of cystic fibrosis (CF).
The three DNA base pairs T-A-G at position 507 of the CFTR nucleotide sequence form the template for the mRNA codon A-U-C for the amino acid isoleucine, while the three DNA base pairs A-A-A at the adjacent position 508 form the template for the codon U-U-U for phenylalanine. The ΔF508 mutation is a deletion of the G pair from position 507 along with two A-A pairs from position 508, leaving the DNA sequence T-A-A at position 507 forming the codon A-U-U. Since A-U-U also codes for isoleucine, position 507's amino acid is unchanged, and the mutation's net effect is equivalent to a deletion ("Δ") of the sequence resulting in the codon for phenylalanine ("F") at position 508.
ΔF508 is present in approximately one in 30 Caucasians. Scientists have estimated that the mutation occurred over 52,000 years ago in Northern Europe. One hypothesis as to why the otherwise detrimental mutation has evolved is that it exerts a positive effect by reducing water-loss during cholera, a common cause of death in Europe when the mutation first appeared. 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 into epithelial cells.
The CFTR protein—when in the proper position—opens channels in the cell membrane which release chloride ions out of respiratory epithelial cells. This causes osmosis to draw water out of the cell. The ΔF508 mutation can prevent the CFTR from moving into its proper position in the cell.
Being a heterozygous carrier (having a single copy of ΔF508) results in decreased water loss during diarrhea. This prevents dehydration, and vastly increases the chances of surviving cholera. This same effect may occur during Typhoid Fever, leading to heterozygote advantage and an increase in the frequency of this mutation.
If two carriers of the gene mate, their offspring will have a 25% chance of having two copies of the mutation (see also Mendelian inheritance). Generally ΔF508 carriers are symptom free, however when combined with other mutations, varying degrees of CF-like symptoms can appear (see below).
Having a homozygous pair of genes with the ΔF508 mutation prevents the CFTR protein from obtaining its normal position in the cell membranes. This causes increased water retention in cells, and a variety of effects on the body:
- Thicker mucous membranes in many parts of the body
- Congenital Bilateral Absence of the Vas deferens (CBAVD) due to increased mucus thickness during fetal development
- Pancreatic insufficiency, due to blockage of the pancreatic duct with mucus
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 Double ΔF508 (this varies widely by region). The remaining cases are caused by combinations of that and over 1000 other mutations including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or ΔF508, cause CF symptoms. The genotype is not strongly correlated with severity of the CF, however specific symptoms have been linked to certain mutations.
- Bobadilla, JL; Macek Jr, M; Fine, JP; Farrell, PM (2002). "Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening". Human Mutation 19 (6): 575–606. doi:10.1002/humu.10041. PMID 12007216.
- "Cystic Fibrosis Research Directions". National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).