Delta-F508
ΔF508 is a specific mutation within the human genome. The mutation--a deletion of three base pairs (T, T, T) which form the codon for phenylalanine (F) at the 508 position--prevents a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) from obtaining its normal position. Having two copies of this mutation, inherited from both parents, is the leading cause of cystic fibrosis (CF).
Prevalence
ΔF508 is present in approximately one in 30 caucasians. Scientists have estimated that the mutation occurred over 52,000 years ago in Northern Europe. From an evolutionary standpoint the mutation's negative effects (see below) are outweighed by the fact that it reduces water-loss during cholera, a common cause of death in Europe when the mutation first appeared.
Effects
The CFTR protein--when in the proper position--opens channels in the cell wall which release chloride ions in the 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.
Heterozygous carriers
Being a '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.
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).
Homozygous genotype
Having a 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 500 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.