What Is Cystic Fibrosis?
Cystic fibrosis (CF) is one of the most common serious inherited diseases in people of European descent, though it affects all ethnic groups. It primarily damages the lungs, digestive system, and other organs by causing a buildup of thick, sticky mucus. Understanding CF starts at the molecular level — with a single gene and its many possible mutations.
The Genetic Cause: The CFTR Gene
CF is caused by mutations in the CFTR gene (cystic fibrosis transmembrane conductance regulator), located on chromosome 7. The CFTR protein is a channel that sits in cell membranes and regulates the flow of chloride ions — and by extension, water — in and out of cells. When CFTR is defective, this ion transport fails, causing the secretions of the lungs, pancreas, intestines, and other organs to become abnormally thick.
There are over 2,000 known CFTR mutations, but they vary enormously in their effects. The most common, called F508del (or ΔF508), accounts for the majority of CF cases worldwide. It results from the deletion of three base pairs, causing the loss of a single amino acid (phenylalanine at position 508) in the CFTR protein, which then misfolds and is destroyed before it reaches the cell surface.
Inheritance Pattern: Autosomal Recessive
CF follows an autosomal recessive inheritance pattern. This means:
- A person must inherit two defective copies of the CFTR gene (one from each parent) to develop CF.
- People with only one mutant copy are called carriers — they are generally unaffected but can pass the mutation to their children.
- When both parents are carriers, each pregnancy has a 25% chance of resulting in a child with CF, a 50% chance of a carrier, and a 25% chance of inheriting two normal copies.
How CFTR Mutations Cause Symptoms
CFTR mutations are classified into several classes based on how they disrupt protein function:
| Class | Problem | Example Mutation |
|---|---|---|
| I | No protein produced | G542X (nonsense mutation) |
| II | Protein misfolded, degraded | F508del |
| III | Protein reaches surface but doesn't open | G551D |
| IV | Protein opens but conducts poorly | R117H |
| V | Reduced amount of normal protein | 3849+10kbC→T |
In the lungs, defective CFTR leads to dehydrated airway surfaces, impaired mucociliary clearance, and chronic bacterial infections — the main driver of lung disease and the leading cause of death in CF patients.
Diagnosis
CF is now detected through newborn screening programs in many countries, typically using a blood test to measure immunoreactive trypsinogen (IRT) followed by CFTR genetic testing. Sweat chloride testing remains the gold standard confirmatory test — elevated chloride levels in sweat are a hallmark of CF.
Modern Treatments: From Symptomatic to Targeted
For decades, CF treatment focused on managing symptoms — airway clearance, antibiotics, nutritional support. The landscape changed fundamentally with the development of CFTR modulators: small molecules that target the underlying protein defect rather than just its consequences.
- Potentiators (e.g., ivacaftor) help defective CFTR channels that reach the cell surface open more effectively — effective for Class III mutations like G551D.
- Correctors (e.g., lumacaftor, tezacaftor, elexacaftor) help misfolded CFTR (especially F508del) fold properly and reach the cell membrane.
- Combination therapies like Trikafta (elexacaftor/tezacaftor/ivacaftor) combine a corrector and potentiator and are effective for approximately 90% of people with CF who have at least one F508del allele.
These therapies represent a revolution in CF care, dramatically improving lung function and quality of life. Gene therapy and RNA-based approaches are also under active investigation as potential future cures that address the root genetic cause directly.