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3 - Cystic fibrosis: the quest for a cure page 3
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2. The CF gene and its protein Link to the Medical Research Council web site

Figure 2. Roll your cursor over the highlighted words to see the sequence of diagrams.
Finding the gene
Early studies of people with cystic fibrosis (CF), carried out in the 1950s, strongly suggested that something was wrong with the transport of salt (sodium chloride). Then, in the early 1980s, researchers showed that the outer membranes of cells from people with CF are poorly permeable to chloride ions (Cl-), but biochemical analyses failed to identify the defective protein. Genetic studies provided the next breakthrough in 1985, by pinpointing the mutation to a small region on chromosome 7.
The basics
The basic defect in CF arises particularly in the epithelial cells lining the airways of the lung (Figure 2). There are channels in these lining cells through which ions can pass. Normally, the movements of ions brings water to the surface of the airway and keeps the mucus moist. The defective gene acts to block the channels, which causes the mucus to dry out. It is then difficult for a person to shift the mucus, which then becomes prone to infection by bacteria.

Let's look at this in more detail.

Figure 3. Roll your cursor over the highlighted words to see the sequence.
How do the channels keep the mucus moist?
Look at figure 3. The lining cells have channels on their outside surface (on the side of the airway). One of the channels allows sodium ions to flow into the cell and the other controls the passage of chloride ions out of the cell into the mucus on the airway surface. Along with the ion pump, the action of the channels results in an excess of chloride ions in the mucus; i.e. an ionic gradient is set up, with a higher concentration towards the outside. In an attempt to equalise the salt concentrations, water is dragged out through the gaps between the cells and this keeps the mucus moist.
 What happens in CF?
In the lining cell of a person with CF, the vital chloride channel is blocked. This means that there is no movement of chloride ions into the mucus. With no ionic gradient, there is no need for water to move towards the surface and the mucus dries out.

Figure 5 . Roll your cursor over the highlighted stages on the right to see the sequence of diagrams.
How does the chloride channel work?
  The chloride channel is made from a protein called CF transmembrane regulator (CFTR) protein. Its normal function is to control the flow of chloride ions from the cell.

Figure 4 shows a section through the cell membrane of a lining (epithelial) cell. The CFTR protein is embedded in the cell membrane, forming a channel. It is 1480 amino acids long and it has carbohydrate side-chains attached. The R-domain can bind phosphate groups and, together with two adjacent sites which bind and cleave ATP, regulates the opening and closing of the channel. This is shown in figure 5.

Figure 4. Section through the cell membrane of an epithelial cell. The CFTR channel is shown open.
The operation of the CFTR channel
Stage 1 The channel is closed
Stage 2 Phosphate groups (P) add to the R-domain. Cyclic AMP (cAMP) stimulates the enzyme, protein kinase (PKA), to add the phosphate groups.
Stage 3 ATP is bound . . .
Stage 4 . . . and hydrolysed to ADP+Pi
Stage 5 The shape of CFTR changes, opening the Cl- channel.

In cystic fibrosis, the flow of chloride ions and of sodium ions (Na+) is fundamentally altered as shown in Figure 3.

The genetic breakthrough
The final breakthrough came in 1989, when the defective gene responsible for CF was isolated. This was heralded as 'one of the most significant discoveries in the history of human genetics'. It led directly to improved diagnosis of the disorder and has improved the genetic counselling offered to affected families.

CF is complicated: not all cases of the disease are caused by the same genetic defect. Some 800 different mutations have been identified in the CF gene, each affecting the proper functioning of CFTR.

The mutations have various effects. In some instances, no CFTR at all is synthesised; in others, it fails the cell's quality control mechanism and becomes stuck in the endoplasmic reticulum, never reaching the membrane. In yet other cases, the protein may be present in the cell membrane, but may not function correctly.

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