All the characteristics of cystic fibrosis — from the lung infections, to the digestive difficulties, to the salty skin — arise from a mutation in a single gene on chromosome 7. This gene contains instructions for building a protein called the cystic fibrosis transmembrane conductance regulator. That's quite a mouthful, so we'll just call it CFTR for short. When there is no mutation in the gene, the instructions produce a CFTR that sits in the membrane of certain cells and controls the passage of chloride ions in and out of the cell. When the gene is mutated, as it is in people with CF, the faulty instructions produce a CFTR that doesn't work, and chloride ions can not pass through the membrane. In some cases, CFTR doesn't work because it won't open, as shown below. But in 70 to 80 percent of CF cases in the United States, CFTR doesn't work because it's completely missing from the membrane! This radical change in the membrane is caused by a very small change in the CFTR gene. Only three letters of code — out of the gene's total of 6100 — have disappeared. But without this triplet, the instructions for putting the amino acid phenylalanine in position 508 in CFTR are missing. (Thus, the name of this mutation is delta-F508). A shortened CFTR is made, but the cell's quality-control system sees this as an error as the protein prepares to travel from its birthplace (the endoplasmic reticulum) to the cell membrane. 

Quality-control flags the protein for destruction. A missing (or malfunctioning) CFTR has many different effects on the body.  In the sweat glands, the missing protein causes the production of saltier sweat.  Sweat production begins in the tangled end of the gland where cells secrete water into the gland's duct. As the sweat rises toward the skin, cells lining the upper duct reabsorb sodium (   ) and chloride (   ) ions, and other molecules in the sweat. When CFTR is missing, chloride ions are not reabsorbed. The loss of CFTR also stops the reabsorption of sodium ions, and the sweat that leaves the body is five times saltier than normal. The loss of so much salt alters the balance of ions in the blood and can lead to abnormal heart rhythms. CFTR also shuttles chloride ions in other organs, including the pancreas, where it ultimately prevents digestive enzymes from reaching the intestine. Cells in the pancreas produce digestive enzymes and secrete them into the pancreatic duct for export to the intestine. The chloride-pumping actions of CFTR cause water to follow the chloride into the duct, where the watery slurry flows out of the duct and into the intestine carrying the enzymes. When CFTR is missing, the chloride and water stay in the cells.  There is no slurry to carry the enzymes away, so the enzymes begin to digest the pancreas itself. This leads to inflammation, and thick mucus plugs the duct. The organ that suffers most from the missing CFTR, though, is the lung. It is not exactly clear how the absence of CFTR leads to lung damage, but mucus in the lung becomes very thick.

  The lung becomes prone to bacterial infection because this mucus can support bacterial growth. The thick mucus is hard to clear so it builds up in the bronchioles and reduces the surface available for oxygen exchange. At the same time, infections damage lung tissue when the body's own immune cells release enzymes to kill the bacteria.  The enzymes incidentally kill lung cells, so chronic infections seriously damage the lung. The severity of symptoms in CF varies from person to person, but over 90% of people with CF have measurably saltier sweat than people without CF.  Doctors use the "sweat test" — which measures the amount of salt in the sweat — to diagnose most cases. Sweat is collected from the forearm with the help of a weak electric current and a sweat-inducing chemical called pilocarpine.  An electrode filled with pilocarpine is placed on the inner forearm, while the other electrode is placed on the outer forearm.  Current runs for five minutes — making the arm feel tingly or warm — to deliver the pilocarpine under the skin. Once the electrodes are removed and the arm rests for four minutes, a piece of filter paper soaks up the sweat where the pilocarpine-filled electrode was attached.  The filter paper is placed into a flask after 30 minutes of sweat collection, and the sweat is rinsed from the filter. A machine called a digital chloridometer measures the concentration of chloride ions in the sample.  A reading above 60 mmol/liter indicates the person has CF. In cases where the sweat test is inconclusive or impossible to administer (as in infants), genetic testing can diagnose the disorder.  Because there are over 900 mutations that can cause CF, geneticists begin testing by searching for the most common mutation – deltaF508. Delta F508 is named for the missing phenylalanine (F) at position 508 in the CFTR protein.  The corresponding mutation is a deletion of three bases — CTT — near the beginning of the gene. A DNA test detects this mutation through the use of small molecules called primers.  As shown below, the blue primer attaches to the DNA on the left side of the deletion, and the green primer attaches to the right. If the gene does not have this deletion, the blue primer attaches to the left, but the green primer fails to attach. In essence, when both primers attach to the gene, a process called PCR makes millions of copies of the short DNA sequence that lies between the two primers. This means the tube containing a gene with the delta F508 mutation produces lots of DNA copies, while a tube containing a gene with another mutation (or no mutation) produces nothing. Though we can see this difference in this drawing, in real life the geneticist must concentrate the DNA pieces in one spot in a gel and dye it before he can see the results. The white spot on the left contains the dyed DNA pieces of a person with the delta F508 mutation.  The lack of a spot on the right shows a second person does not have this mutation.  The geneticist must continue looking for the second person’s mutation with additional DNA tests. Once the mutation (or mutations if the person has two different types) is identified, the same genetic test can be used on relatives to determine if other family members carry the same mutation. These genetic tests can also detect the carrier status of people who have no known relatives with CF.  However, because it is impossible to test for all of the 900 mutations that cause CF, carrier testing is not 100% sensitive.  In the American Caucasian population, testing is 89% sensitive, that is, testing will detect 89 out of 100 CF carriers. CF is an inherited disorder and is not contagious.  A person gets CF when he/she inherits TWO mutated CFTR genes, one from each parent.  The CFTR gene resides on chromosome 7. The child receives one of his chromosome 7s from his father's sperm, and one from his mother's egg.  

If both of these chromosomes have a mutated CFTR gene (represented by the green spot), he will develop CF. His parents do not have CF because they both have a normal copy of the gene on their other chromosome.  CF only develops when a person has two copies of the mutated gene, and is, therefore, a recessive disorder. When both parents carry a mutation in the CF gene, each child has a 1-in-4 chance of having CF.  To see why, we first represent the parental genes with letters:  C represents the normal gene, and c represents the mutated gene.Then we set up a Punnett square by arranging each parent's genes on the outer edges of the square. Each parent donates one of their two CFTR genes to the child, so we place one of the father's genes and one of the mother's genes into each box.  Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations. Next, we count the boxes that contain a CF-causing genotype (the cc combo).  1 out of 4 boxes contain this combo, so the chance of this couple's child developing CF is also 1 out of 4, or 25%.The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 25% chance of developing CF. In this family, one in four children has cystic fibrosis.  Other couples with the mutation may have two, three, four, or even no children with the disorder. If you are a man or woman with CF, your odds of passing CF to your child are greater if your partner also carries a mutated CFTR gene.  In the Punnett square below, the woman has CF (cc), but the results are the same if the man has CF instead. There are two boxes with the cc genotype, so every child of this couple has a 50% chance of inheriting cystic fibrosis. If your partner does not carry a mutated CFTR gene, there is no chance any of your children will inherit cystic fibrosis.  (In this case, the father has CF and the mother doesn't carry the gene). Cystic fibrosis is a recessive disorder.  That is, a person gets cystic fibrosis only when he or she inherits two copies of the mutated gene, one from each parent. Children should be tested for cystic fibrosis if they have persistent diarrhea, smelly and greasy stool, frequent pneumonia, chronic coughing, salty skin, or poor growth. Cystic fibrosis (CF) affects about 1 in 2,500 births in the U.S. and it affects males and females equally.  About 5% of the U.S. population are unaffected carriers of the disorder. CF is most common in Caucasians (1 in 3,300) and some Native Americans (Pueblo: 1 in 4,000; Zuni: 1 in 1,500).  It is less common in Americans of Hispanic (1 in 8,000), African (1 in 15,000, and Asian (1 in 32,000) descent. People with cystic fibrosis have saltier sweat than others, so, the simple and inexpensive "sweat test" that measures the amount of salt in a person's sweat, is used for diagnosis.  Carriers of the cystic fibrosis gene can be detected with DNA testing, but the test can only pick up 80 to 85 percent of carriers of northern European descent.

 Cystic fibrosis occurs when a genetic mutation stops the production of a protein in cells of the lung, pancreas, and other organs.  The absence of the protein impairs the cell's ability to transport chloride ions into and out of the cell.  This sets up secondary conditions, including the thick mucus and bacterial infections in the lung. Nutritional problems from the lack of digestive enzymes are usually solved with enzyme supplements.  Lung problems are treated, but not cured, with chest percussions or other methods of clearing mucus, drugs that help break up the mucus, and antibiotics.  When the lungs begin to fail, a lung transplant can extend life. Early signs of CF: Chronic respiratory and digestive problems are frequently the first signs of CF. Prognosis: With today’s treatments, prognosis is steadily improving year by year. The CF Lung: Mucus & Infection: Dr. Clement Ren describes the reasons why the lungs become infected and produce thick mucus. The CF Lung: Inflammation: Damage to the lung occurs not from the bacterial infection itself, but from the inflammation caused by the immune system’s attack on the bacteria. Variability of CF: Dr. Ren discusses the wide range of symptoms in CF and the varying severity from person to person. Treatments: Present and Future: The mainstays of CF treatment include moving mucus out of the lungs and using antibiotics to control infection. Care at CF Centers: Frequent check-ups at CF centers make sure the child is eating well and the lungs are functioning well. Course of Bacterial Infections: The bacteria that infect the people with CF change as the person ages. B. cepacia: Though infection with this bacteria is not very common, it is much more aggressive than more common bacterial infections. Lung Transplant: A transplant is an option after the lungs have become badly damaged. As CF Population Ages: With more and more people with CF living into the middle age, diabetes and osteoporosis become additional problems. Can people with CF have kids? Hundreds of women with CF in the United States have had children, but men are usually infertile and need in-vitro services. CF and Ethnicity: Some ethnic groups have higher incidences of CF, but no one really knows why. How is cystic fibrosis treated? What is it like to have cystic fibrosis? Feelings at Diagnosis: Getting updated information can help lessen the devastating feelings that come after diagnosis. Treating a 2-year-old: The challenges of treating a 2-year-old with CF. Daily Treatments: Fitting vest sessions or chest percussions into the daily routine. Struggling with Weight: Supplements can help children with CF gain needed pounds but they’re not always interesting to eat. Doctor Visits: How many times the child need to see the CF doctors and what goes on during visits. Telling Child about CF: What does a 6-year-old with CF need to know about her disorder. Physical Activity: CF doesn’t have to limit the child’s physical activities, but the child should control his or her level of participation. Child’s Feelings: Helping a child with CF deal with the attention of other children and feelings of unfairness. Siblings: Parents try to share their attention equally among all children. School Interaction: Interacting with the child’s class at the beginning of the school year can remove the stigma of being different and alert the teacher to the child’s specific needs. Having More Children: Issues the Sneddons Faced when they considered having another child. Support Groups: Through support groups organized by the Cystic Fibrosis Foundation, you can meet other people with CF or other parents.