The cystic fibrosis transmembrane conductance regulator (CFTR) is defective in cystic fibrosis (CF). This protein is a channel that sits on the surface of cells and transports chloride and other molecules, such as bicarbonate. The gene that encodes the CFTR protein, which is also called CFTR, is located on chromosome 7. Mutations in this gene lead to CF. Since the discovery of the CFTR gene in 1989, more than 2,500 mutations have been identified.
Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs, digestive system and other organs in the body.
Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with CF, a defective gene causes the secretions to become sticky and thick. Instead of acting as lubricants, the secretions plug up tubes, ducts and passageways, especially in the lungs and pancreas.
Although cystic fibrosis is progressive and requires daily care, people with CF are usually able to attend school and work. They often have a better quality of life than people with CF had in previous decades. Improvements in screening and treatments mean that people with CF now may live into their mid- to late 30s or 40s, and some are living into their 50s.
The CFTR protein is composed of 1,480 amino acids—the building blocks of all proteins—and is located on the surface of many cells in the body. The CFTR protein contains a single chain of amino acids that are grouped in five functional regions called domains. Two transmembrane domains (TMD1 and TMD2), two cytoplasmic nucleotide-binding domains (NBD1 and NBD2) and a regulatory (R) domain make up the CFTR protein. Each domain has a special function when it comes to transporting chloride through the cell surface. Therefore, mutations in different domains cause a range of CF symptoms depending on the extent that chloride transport is affected. Mutations in CFTR often affect the three-dimensional structure of the protein and prevent CFTR from reaching the membrane.
The location of the CFTR protein, which is found in several organs, determines where the symptoms of CF occur. The organs that are typically involved in CF are the skin, pancreas and lungs.
Sweat Gland
People with CF has very salty sweat. The sweat gland secretes salt and water some of which is typically reabsorbed in the sweat duct. This reabsorption process is markedly abnormal in people with CF. Chloride transport is virtually eliminated because CFTR located on the surface of the cells in the sweat duct is defective. The lack of CFTR function leads to excess chloride in the sweat of people with CF. The high chloride concentration in the sweat can be used to diagnose people with CF.
Lung
The airways are covered with a thin, layer of liquid called airway surface liquid (ASL) and a mucus gel layer. The mucus layer traps bacteria and foreign particles, while cilia on the surface of airway cells constantly move the particles out of the lungs and toward the mouth. This process, called mucociliary clearance is an important defense mechanism that protects the lungs from infection. The ASL also contains antiproteases, antioxidants, antibodies and other substances that work together to neutralize or destroy invading organisms without damaging the lungs. In CF airways, decreased chloride transport is coupled with excess sodium reabsorption out of the ASL. Since water follows the flow of sodium the ASL and the mucus gel layer become dehydrated.
Pancreas
The exocrine pancreas produces enzymes that digest food. Most people with CF do not make pancreatic enzymes leading to a problem called pancreatic insufficiency. The pancreatic duct cells also secrete bicarbonate into the intestine to neutralize stomach acid via the CFTR channel. The inability to neutralize stomach acid contributes to malabsorption in many people with CF.
Select the “Lung – Airway Cell” or “Sweat Gland Cell” above to compare the functionality of a normal cell to a cell with CF.
Cellular Processing
Construction and placement of the CFTR protein in the cell membrane occurs in distinct phases. Located on the long (q) arm of chromosome 7 at position 31.2, the CFTR gene is comprised of 27 exons that encode its genetic sequence (1). An exon is a portion of a DNA that contains the code for a protein structure. The CFTR gene is transcribed into a single strand of RNA within the cell nucleus (2); regions that are not needed to make the protein are spliced out, producing the final messenger RNA (mRNA) (3).
The mRNA leaves the nucleus (4) and is translated into protein by ribosomes in the endoplasmic reticulum, or ER (5). A number of proteins called chaperones (6), facilitate folding of the new CFTR protein and its to the Golgi apparatus (7) where sugars are added. The CFTR protein then travels (8) to cell surface (9).
Mutations
More than 2500 different mutations in the CFTR gene have been described. Most of these mutations either substitute one base – the building material of DNA – for another, or delete a small number of DNA bases. The most common CFTR mutation, present in approximately 70 percent of people with CF, is F508del. This mutation is caused by the deletion of three base pairs of the CFTR gene leading to the loss of an amino acid called phenylalanine, abbreviated F, in the CFTR protein.
Everyone receives one copy of the CFTR gene from each parent. To have CF, a mutation must be present on both copies of the CFTR gene, but the mutations do not have to be the same. If a person received one normal gene and one mutated gene, he or she will not have CF, but will be a CFTR mutation “carrier”. One in 31 Americans has one CFTR gene mutation.
Mutations in the CFTR gene can lead to different changes in the CFTR protein. These changes are grouped into 6 classes. People with CF who have some residual CFTR function (Classes 4, 5 & 6) tend to have milder or later onset of symptoms.
Six functional classes of CFTR gene mutations have been described
Class 1 mutations
No CFTR protein is produced. Class 1 mutations can be due to early termination of CFTR protein production or large regions of mutated CFTR DNA.
Class 2 mutations
Defective trafficking of CFTR, which does not reach the surface of the cell. F508del is a class 2 mutation.
Class 3 mutations
The CFTR protein reaches the cell surface but it does not function. G551D is a class 3 mutation.
Class 4 mutations
The CFTR protein reaches the cell surface but chloride transport through the channel is defective.
Class 5 mutations
The CFTR channel is normal but the amount of protein at the cell surface is decreased.
Class 6 mutations
The CFTR channel is not stable at the cell surface so the amount of protein at the cell surface is decreased.
Effects on Other Channels
When CFTR is defective other channels, including the outwardly rectifying chloride channel (ORCC), the epithelial sodium channel (ENaC), a potassium channel known as ROMK1 and a chloride/bicarbonate exchanger, do not work properly. In addition, other chloride channels present on the surface of epithelial cells may be affected in the CF airways. These “alternative” chloride channels have been proposed as a therapeutic target to enhance chloride transport.
The ORCC is found on the surface of many epithelial cells. Normal CFTR facilitates the transport of adenosine triphosphate (ATP), an energy-carrying molecule, to the outside of the cell, activating ORCC. It is unknown whether CFTR itself or an associated channel actually transports the ATP. However, the mutant CFTR is not able to perform the function of transporting ATP.
The ENaC, a sodium channel found on the surface of epithelial cells, is made up of four subunits: two alpha, one beta and one gamma. Each subunit consists of two transmembrane helices. CFTR also influences the function of ENaC in the lung by decreasing its activity, however, the mechanism by which this occurs is unclear.
As suggested by its name, the chloride/bicarbonate exchanger transports one bicarbonate molecule out the cell for every chloride that it transports into the cell. The chloride is derived from the efflux of chloride through CFTR. Therefore, if CFTR is not functional the activity of this channel will be greatly reduced.
Several other chloride channels are present on the cell surface. The one that may be most influenced by CFTR is the CaCC or calcium-activated chloride channel. The exact protein that creates this channel has yet to be defined. However, it is known that the channel is modulated by the P2Y2 receptor which is activated by ATP. Therefore, the activity of this channel could be influenced by decreased ATP associated with mutant CFTR..
Symptoms
In the U.S., because of newborn screening, cystic fibrosis can be diagnosed within the first month of life, before symptoms develop. But people born before newborn screening became available may not be diagnosed until the signs and symptoms of CF show up.
Cystic fibrosis signs and symptoms vary, depending on the severity of the disease. Even in the same person, symptoms may worsen or improve as time passes. Some people may not experience symptoms until their teenage years or adulthood. People who are not diagnosed until adulthood usually have milder disease and are more likely to have atypical symptoms, such as recurring bouts of an inflamed pancreas (pancreatitis), infertility and recurring pneumonia.
People with cystic fibrosis have a higher than normal level of salt in their sweat. Parents often can taste the salt when they kiss their children. Most of the other signs and symptoms of CF affect the respiratory system and digestive system.
Respiratory signs and symptoms
The thick and sticky mucus associated with cystic fibrosis clogs the tubes that carry air in and out of your lungs. This can cause signs and symptoms such as:
- A persistent cough that produces thick mucus (sputum)
- Wheezing
- Exercise intolerance
- Repeated lung infections
- Inflamed nasal passages or a stuffy nose
- Recurrent sinusitis
Digestive signs and symptoms
The thick mucus can also block tubes that carry digestive enzymes from your pancreas to your small intestine. Without these digestive enzymes, your intestines aren't able to completely absorb the nutrients in the food you eat. The result is often:
- Foul-smelling, greasy stools
- Poor weight gain and growth
- Intestinal blockage, particularly in newborns (meconium ileus)
- Chronic or severe constipation, which may include frequent straining while trying to pass stool, eventually causing part of the rectum to protrude outside the anus (rectal prolapse)
When to see a doctor
If you or your child has symptoms of cystic fibrosis — or if someone in your family has CF — talk with your doctor about testing for the disease. Consult a physician who is knowledgeable about CF.
Cystic fibrosis requires consistent, regular follow-up with your doctor, at least every three months. Contact you doctor if you experience new or worsening symptoms, such as more mucus than usual or a change in the mucus color, lack of energy, weight loss, or severe constipation.
Seek immediate medical care if you're coughing up blood, have chest pain or difficulty breathing, or have severe stomach pain and distention.
Causes
In cystic fibrosis, a defect (mutation) in a gene — the cystic fibrosis transmembrane conductance regulator (CFTR) gene — changes a protein that regulates the movement of salt in and out of cells. The result is thick, sticky mucus in the respiratory, digestive and reproductive systems, as well as increased salt in sweat.
Many different defects can occur in the gene. The type of gene mutation is associated with the severity of the condition.
Children need to inherit one copy of the gene from each parent in order to have the disease. If children inherit only one copy, they won't develop cystic fibrosis. However, they will be carriers and could pass the gene to their own children.
Risk factors
Because cystic fibrosis is an inherited disorder, it runs in families, so family history is a risk factor. Although CF occurs in all races, it's most common in white people of Northern European ancestry.
Complications
Complications of cystic fibrosis can affect the respiratory, digestive and reproductive systems, as well as other organs.
Respiratory system complications
- Damaged airways (bronchiectasis). Cystic fibrosis is one of the leading causes of bronchiectasis, a chronic lung condition with abnormal widening and scarring of the airways (bronchial tubes). This makes it harder to move air in and out of the lungs and clear mucus from the bronchial tubes.
- Chronic infections. Thick mucus in the lungs and sinuses provides an ideal breeding ground for bacteria and fungi. People with cystic fibrosis may often have sinus infections, bronchitis or pneumonia. Infection with bacteria that is resistant to antibiotics and difficult to treat is common.
- Growths in the nose (nasal polyps). Because the lining inside the nose is inflamed and swollen, it can develop soft, fleshy growths (polyps).
- Coughing up blood (hemoptysis). Bronchiectasis can occur next to blood vessels in the lungs. The combination of airway damage and infection can result in coughing up blood. Often this is only a small amount of blood, but it can also be life-threatening.
- Pneumothorax. In this condition, air leaks into the space that separates the lungs from the chest wall, and part or all of a lung collapses. This is more common in adults with cystic fibrosis. Pneumothorax can cause sudden chest pain and breathlessness. People often feel a bubbling sensation in the chest.
- Respiratory failure. Over time, cystic fibrosis can damage lung tissue so badly that it no longer works. Lung function usually worsens gradually, and it eventually can become life-threatening. Respiratory failure is the most common cause of death.
- Acute exacerbations. People with cystic fibrosis may experience worsening of their respiratory symptoms, such as coughing with more mucus and shortness of breath. This is called an acute exacerbation and requires treatment with antibiotics. Sometimes treatment can be provided at home, but hospitalization may be needed. Decreased energy and weight loss also are common during exacerbations.
Digestive system complications
- Nutritional deficiencies. Thick mucus can block the tubes that carry digestive enzymes from your pancreas to your intestines. Without these enzymes, your body can't absorb protein, fats or fat-soluble vitamins, so you can't get enough nutrients. This can result in delayed growth, weight loss or inflammation of the pancreas.
- Diabetes. The pancreas produces insulin, which your body needs to use sugar. Cystic fibrosis increases the risk of diabetes. About 20% of teenagers and 40% to 50% of adults with CF develop diabetes.
- Liver disease. The tube that carries bile from your liver and gallbladder to your small intestine may become blocked and inflamed. This can lead to liver problems, such as jaundice, fatty liver disease and cirrhosis — and sometimes gallstones.
- Intestinal obstruction. Intestinal blockage can happen to people with cystic fibrosis at all ages. Intussusception, a condition in which a segment of the intestine slides inside an adjacent section of the intestine like a collapsible telescope, also can occur.
- Distal intestinal obstruction syndrome (DIOS). DIOS is partial or complete obstruction where the small intestine meets the large intestine. DIOS requires urgent treatment.
Reproductive system complications
- Infertility in men. Almost all men with cystic fibrosis are infertile because the tube that connects the testes and prostate gland (vas deferens) is either blocked with mucus or missing entirely. Certain fertility treatments and surgical procedures sometimes make it possible for men with CF to become biological fathers.
- Reduced fertility in women. Although women with cystic fibrosis may be less fertile than other women, it's possible for them to conceive and to have successful pregnancies. Still, pregnancy can worsen the signs and symptoms of CF, so be sure to discuss the possible risks with your doctor.
Other complications
- Thinning of the bones (osteoporosis). People with cystic fibrosis are at higher risk of developing a dangerous thinning of bones. They may also experience joint pain, arthritis and muscle pain.
- Electrolyte imbalances and dehydration. Because people with cystic fibrosis have saltier sweat, the balance of minerals in their blood may be upset. This makes them prone to dehydration, especially with exercise or in hot weather. Signs and symptoms include increased heart rate, fatigue, weakness and low blood pressure.
- Mental health problems. Dealing with a chronic illness that has no cure may cause fear, depression and anxiety.
Prevention
If you or your partner has close relatives with cystic fibrosis, you both may choose to have genetic testing before having children. The test, which is performed in a lab on a sample of blood, can help determine your risk of having a child with CF.
If you're already pregnant and the genetic test shows that your baby may be at risk of cystic fibrosis, your doctor can conduct additional tests on your developing child.
Genetic testing isn't for everyone. Before you decide to be tested, you should talk to a genetic counselor about the psychological impact the test results might carry.
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