Cystic fibrosis, or CF, is a progressive genetic disease inherited when a child receives a mutated gene from both parents. The condition impacts the body’s production of mucus and sweat. In individuals with CF, these secretions, which are normally thin and lubricating, become thick and sticky. This change leads to health complications, particularly affecting the respiratory and digestive systems, with the cause found at the cellular level.
The CFTR Protein and Normal Function
At the center of cystic fibrosis is a protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This protein is a channel in the outer membrane of epithelial cells, which line organs and produce fluids like mucus, sweat, and digestive enzymes. The CFTR gene on chromosome 7 holds the instructions for building this protein.
The CFTR protein’s main job is to allow chloride ions to move out of the cell. This movement of chloride is important for maintaining fluid balance on the cell’s surface. When chloride ions exit, they create an electrical gradient that draws sodium ions to follow. This increase in salt concentration outside the cell pulls water to the surface through osmosis.
This water movement keeps mucus thin and slippery, protecting the linings of the airways and digestive system. In sweat glands, the CFTR channel works in reverse, moving chloride from the sweat into cells to conserve salt.
Activation of the CFTR Channel
The CFTR protein channel is not always open; it requires molecular signals to activate. This cell signaling pathway begins when a molecule, such as a hormone, binds to a receptor on the cell’s surface. This binding triggers a chain reaction inside the cell, starting with the activation of an enzyme called adenylyl cyclase.
Activated adenylyl cyclase converts a high-energy molecule called ATP into a “second messenger” known as cyclic AMP (cAMP). The increase in cAMP levels signals another enzyme, Protein Kinase A (PKA), which interacts directly with the CFTR protein to switch it on.
PKA opens the CFTR channel by attaching a phosphate group to the protein’s regulatory domain in a process called phosphorylation. This modification, along with the binding of ATP, causes the CFTR protein to change its shape, physically opening the channel for chloride ions to flow out.
Disruption from Genetic Mutations
Cystic fibrosis is caused by mutations in the CFTR gene. Over 2,500 different mutations in this gene are known, and each disrupts the protein’s function. These mutations are categorized into classes based on the problem they cause, which explains the variability in disease severity.
- Class I mutations are production problems where a premature stop signal in the genetic code prevents a full-length, functional protein from being made.
- Class II mutations are processing problems where the protein is created but misfolded. The cell’s quality control machinery recognizes the defective protein and destroys it before it reaches the cell membrane. The most common CF mutation, F508del, is in this class.
- Class III mutations are gating problems where the protein is in the correct location but fails to open in response to cellular signals.
- Class IV mutations are conductance problems where the channel is in place and opens, but its structure is flawed, preventing chloride ions from flowing through efficiently.
Cellular and Organ-Level Consequences
When genetic mutations break the CFTR signaling pathway, the resulting thick, sticky mucus affects entire organ systems. In the lungs, this dense mucus clogs small airways, making it difficult to breathe. It also creates an environment where bacteria become trapped, leading to a cycle of chronic infections, inflammation, and progressive lung damage.
The pancreas is also severely affected. Thick mucus blocks the ducts that carry digestive enzymes to the small intestine. Without these enzymes, the body cannot properly absorb nutrients from food, leading to malnutrition. In sweat glands, the faulty CFTR channel prevents the reabsorption of chloride, resulting in sweat with a high salt content, which is a primary diagnostic test for CF.
Targeting the Pathway with Modern Therapies
Understanding the CFTR pathway and mutation-specific defects led to the development of drugs known as CFTR modulators. These therapies directly target the faulty protein to restore its function, addressing the underlying cause of the disease. The modulators are grouped based on how they fix the protein, corresponding to the mutation classes.
“Correctors” are drugs designed to help misfolded proteins, such as those from the F508del mutation, fold into the correct 3D shape. This allows the protein to be moved to the cell membrane, addressing the problem in Class II mutations. “Potentiators” work on channels already at the cell surface that are not functioning correctly. These drugs help open the gate for proteins affected by gating (Class III) or conductance (Class IV) mutations, increasing chloride ion flow.
For many patients, a combination of correctors and potentiators is used. This approach first gets the protein to the right place and then ensures it works, leading to significant improvements in health.