Cystic fibrosis is caused by mutations in a single gene called CFTR, which controls the movement of salt and water across cell surfaces throughout the body. It takes two copies of the mutated gene, one inherited from each parent, to cause the disease. More than 2,000 different mutations in this gene have been identified, but one specific mutation accounts for the vast majority of cases.
The CFTR Gene and What It Does
The CFTR gene provides instructions for building a protein that acts as a channel on the surface of cells lining the lungs, pancreas, sweat glands, and digestive tract. This channel lets chloride ions (a component of salt) flow out of cells. That chloride movement creates a pull that draws sodium and water to the cell surface, keeping the thin layer of fluid coating these organs properly hydrated.
When the CFTR protein works normally, it does two critical things at once: it secretes chloride out of cells, and it puts the brakes on a separate sodium channel that would otherwise absorb too much sodium (and therefore too much water) back into the cell. The result is a balanced, watery layer of mucus that flows freely, trapping and clearing bacteria, lubricating the pancreatic ducts, and allowing sweat glands to reabsorb salt properly.
When both copies of the gene are mutated, this protein is either missing, misshapen, or doesn’t reach the cell surface. Without it, chloride can’t get out, sodium absorption goes into overdrive, and water gets pulled away from the mucus layer. The mucus becomes dehydrated, thick, and sticky, setting the stage for the complications that define cystic fibrosis.
How CF Is Inherited
Cystic fibrosis follows an autosomal recessive inheritance pattern. “Autosomal” means the gene sits on one of the 22 non-sex chromosomes, so males and females are equally affected. “Recessive” means you need two defective copies to develop the disease. A person with just one mutated copy is a carrier: they produce enough working CFTR protein to stay healthy but can pass the mutation to their children.
When both parents are carriers, each pregnancy carries a 25% chance the child will have cystic fibrosis, a 50% chance the child will be a carrier like the parents, and a 25% chance the child will inherit two normal copies of the gene. These odds reset with every pregnancy. Two carrier parents could have four children with CF, or none, purely by chance.
The Most Common Mutation
Of the thousands of known CFTR mutations, one dominates. A mutation called F508del, where a tiny piece of the gene’s code is deleted, appears in roughly 90% of people with cystic fibrosis. About half of all CF patients carry two copies of F508del (one from each parent), while the rest carry F508del paired with a different mutation on their other chromosome. The F508del mutation causes the CFTR protein to fold incorrectly, so the cell’s quality-control system destroys it before it ever reaches the surface.
Other mutations work differently. Some produce a CFTR protein that reaches the cell surface but doesn’t open properly. Others create a channel that opens but doesn’t stay open long enough. Still others prevent the gene from producing any protein at all. The type of mutation influences disease severity, which is why two people with cystic fibrosis can have very different experiences.
How Thick Mucus Develops
The chain of events from gene mutation to disease symptoms starts with salt and water. When CFTR doesn’t work, chloride stays trapped inside cells, and sodium absorption ramps up unopposed. Water follows sodium, so the thin liquid layer coating the airways, called the airway surface liquid, becomes dehydrated. The mucus proteins sitting in that liquid, called mucins, are normally released in a tightly packed form and need water and bicarbonate ions to unfold and expand into a flowing gel. Without enough of either, they stay in a semi-expanded, tangled state.
The problem compounds from there. As the mucus layer loses water, the concentration of mucin proteins rises, and they begin to physically entangle with each other. Inflammation and oxidative stress cause additional chemical bonds to form between mucin strands, stiffening the gel further. The acidic environment created by the loss of bicarbonate transport makes things worse, changing how ions interact within the mucus and promoting the precipitation of other molecules. The end result is mucus that is not just thick but adhesive, forming plaques that cling to airway walls and resist clearance by the tiny hair-like structures (cilia) that normally sweep mucus toward the throat.
Organs Affected Beyond the Lungs
While lung disease gets the most attention, the same salt-and-water imbalance strikes wherever CFTR is expressed.
In the pancreas, CFTR normally helps produce the alkaline fluid that flushes digestive enzymes from the pancreas into the small intestine. Without working CFTR, pancreatic secretions become low in volume, acidic, and protein-heavy. This causes the ducts to clog, initially with abnormal enzyme secretions and eventually with accumulated mucus. Blocked enzymes, particularly those that break down fats and proteins like elastase and chymotrypsin, never reach the intestine. The result is pancreatic insufficiency, where food passes through the gut without being fully digested. The lower pH in the intestine also interferes with bile acid function and can lead to intestinal blockages.
Sweat glands are affected in a different way. CFTR is responsible for reabsorbing chloride from sweat as it travels through the sweat duct. Without it, sweat reaches the skin surface with abnormally high salt content. This is why parents of children with CF sometimes notice their child’s skin tastes salty, and it’s the basis for the primary diagnostic test.
The reproductive system, liver, and sinuses are also affected. Most males with CF are infertile because the ducts that transport sperm are blocked or absent. Thick secretions can obstruct bile ducts in the liver and sinus passages in the skull.
How CF Is Diagnosed
In most countries, cystic fibrosis is now caught through newborn screening before symptoms appear. The screening blood test measures levels of a substance called immunoreactive trypsinogen (IRT), which is produced by the pancreas and tends to be elevated in newborns with CF because of pancreatic duct blockage. If IRT levels are high, a second test on the same blood sample looks for known mutations in the CFTR gene.
A positive screening result doesn’t confirm the diagnosis on its own. The gold standard is the sweat test, which measures the chloride concentration in sweat. A chloride level of 60 mmol/L or higher is diagnostic of cystic fibrosis. Levels below 30 mmol/L make CF unlikely. Results between 30 and 59 mmol/L fall in a borderline range that requires repeat testing or genetic analysis to resolve. Genetic testing can identify the specific CFTR mutations involved, which has become increasingly important for guiding treatment with newer therapies that target specific protein defects.
Who Is Most at Risk
Cystic fibrosis has been reported in 96 countries, with an estimated 188,000 people living with the disease worldwide. Of those, about 112,000 have been formally diagnosed, mostly in countries with established patient registries like the United States, Canada, Europe, Australia, and Brazil. The disease is most common in people of Northern European descent, where carrier rates can be as high as 1 in 25. It occurs less frequently in Hispanic, African American, and Asian populations, though it is increasingly recognized in these groups as screening and awareness improve.
Because carriers show no symptoms, most people don’t know they carry a CFTR mutation until they have a child with CF or undergo genetic testing. Carrier screening is available before or during pregnancy for anyone who wants to assess their risk, regardless of ethnic background.