ΔF508
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ΔF508 is a specific mutation within the human genome. The mutation is a deletion of three base pairs at position 508 in the nucleotide sequence of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The deletion prevents the codon for phenylalanine (F) from obtaining its normal position. Having two copies of this mutation, inherited from both parents, is the leading cause of cystic fibrosis (CF).¹

Mechanism

The ΔF508 human genome mutation is characterized by the deletion of three base pairs in the CFTR nucleotide sequence, causing the loss of the amino acid phenylalanine located at position 508. (Source: Oak Ridge National Laboratory, Human Genome Project website)

The three base pairs A-T-C at position 507 of the CFTR nucleotide sequence form the codon for the amino acid isoleucine, while the three base pairs T-T-T at the adjacent position 508 form the codon for phenylalanine. The ΔF508 mutation is a deletion of the C pair from position 507 along with two T pairs from position 508, leaving the codon A-T-T at position 507 (see figure). Since A-T-T also codes isoleucine, position 507's amino acid is unchanged, and the mutation's net effect is equivalent to a deletion ("Δ") of the codon for phenylalanine ("F") at position 508.²

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.^{citation needed}

Effects

The CFTR protein--when in the proper position--opens channels in the cell wall which release chloride ions out of 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.³

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.^{citation needed} 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).

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.

See also

• Heterozygote advantage

External links

• Types of Cystic Fibrosis at wrongdiagnosis.com

References