Video Production Brief

Cystic Fibrosis
Also known as mucoviscidosis, cystic fibrosis is an autosomal recessive genetic disorder.
This disease affects the pancreas, liver, intestine, and most commonly the lungs.
Gene and Protein Overview
Cystic fibrosis is caused by a mutation in the gene known as cystic fibrosis transmembrane
conductance regulator (CFTR), found at q31.2, of chromosome 7.The CFTR gene creates a
protein that is 1480 amino acids long, located between base pair 117 120 016 to 117 308 718,
on chromosome 7, region 3, band 7, sub band 2. This protein is a chloride ion channel which
assists in the creation of sweat, digestive juices, and mucus. It possesses two ATP
hydrolysing domains, which allows the protein to use energy in the form of ATP; and
possesses two domains with six alpha helices each, which allow protein to cross the cell
membrane. As this gene also relies on phosphorylation to control activity, it contains a
binding site in which phosphate can attach.
Mutation
The most common mutation, F508, is a deletion and affects approximately 70% of people
diagnosed with cystic fibrosis (Davis, 1993). This mutation is a deletion of three nucleotides
that result in a loss of the amino acid phenylaline at position 508 on the protein. F508 is
among more than 150 other mutations. These include missense, nonsense, splice and
frameshift mutations (Davis, 1993).
Mutation most commonly occurs within the first nucleotide binding fold.
Genetics
Most people have two working copies of the CFTR gene, with only one gene needed to
prevent the disease. Therefore cystic fibrosis occurs when neither gene can produce a
functional CFTR protein.
Approximately % of the worlds population are carriers, unaffected people with one
functional, and one mutated CFTR gene. If both parents are carriers the child has 1 in 4
chance of being unaffected, 2 in 4 chance of being a carrier, and 1 in 4 chance of contracting
the disease.
Pathophysiology
Multiple mutation can occur within the CFTR gene, each causing different defects in the
protein. F508 which occurs in over 90% of those who suffer with cystic fibrosis, creates a
protein which does not fold normally and is therefore degraded by the cell. Other mutations
produce proteins that are truncated, do not use energy normally, do not allow chloride, iodide
and thiocyanate to cross the membrane appropriately, or degrade at a faster than normal rate.
The CFTR protein anchors itself to the cytoskeleton of cells in the sweat glands, lungs,
pancreas, and all other exocrine glands in the body. The protein spans the membrane and acts
as a channel controlling the movement of halogens in and out of the cell. This is the case for
all areas the protein is present in the body except the sweat glands, where it facilitates the
movement of chloride from sweat into the cytoplasm.

When a defect is present within the CFTR protein, chloride and thiocyanate cannot exit the
cells in the airway and in the skin. Because chloride is negatively charged, this creates a
difference in the electrical potential inside and outside the cell. Another defect caused by a
CFTR mutation is when the immune defence system is unable to produce hypothiocyanite,
OSCN. Sodium is the most common cation in the extracellular space and the combination of
sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals
with CF. This lost salt forms the basis for the sweat test.
The most significant damage associated with cystic fibrosis is caused by the blockage of
narrow passages of affected organs with thick dehydrated secretions. This excess mucus leads
to infection and remodelling of the lung, damage due to accumulated digestive enzymes in
the pancreas, and blockage of the intestine with thick faeces.
There are several theories on how the defects in the protein and cellular function cause the
clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride,
iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more
viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune
system. Another theory is that the CFTR protein failure leads to a paradoxical increase in
sodium and chloride uptake, which, by leading to increased water reabsorption, creates
dehydrated and thick mucus. Yet another theory is that abnormal chloride movement out of
the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc.