Cystic fibrosis (CF) is a genetic disorder affecting cells throughout the body. It is characterized by the production of abnormally thick and sticky secretions in various organs. The primary issue stems from a malfunctioning protein that disrupts the normal balance of salt and water within and around cells.
The Normal CFTR Protein
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein acts as an ion channel, primarily facilitating the movement of chloride ions across cell membranes. This protein helps maintain the balance of salt and water on various cell surfaces, including those found in the lungs, pancreas, and sweat glands. The CFTR protein is embedded in the outer membrane of epithelial cells.
Its function is to allow chloride ions to flow out of the cell, which then attracts water to the cell surface. This process is crucial for keeping secretions, such as mucus, thin and freely flowing. The CFTR protein also regulates the function of other channels, including those that transport sodium ions. Proper functioning of CFTR ensures that organs like the lungs, pancreas, and intestines can maintain fluid homeostasis.
The Genetic Alteration and Its Impact on CFTR
Cystic fibrosis is caused by genetic alterations in the CFTR gene, located on chromosome 7. These mutations lead to a defective or absent CFTR protein. Over 2,000 different mutations in the CFTR gene have been identified, though only a subset cause cystic fibrosis. The condition results from mutations on both copies of the CFTR gene, one inherited from each parent.
The most common mutation, known as Delta F508 (ΔF508), accounts for approximately 70% of CF cases in the United States. This specific mutation involves the deletion of three base pairs in the CFTR gene, leading to the loss of a phenylalanine amino acid in the protein structure. This deletion impairs the CFTR protein’s ability to fold correctly, preventing its proper transport to the cell surface. The misfolded protein is often degraded by the cell before it can reach its functional location.
Other types of mutations can lead to different problems with the CFTR protein, such as producing proteins that are too short, do not use energy normally, or are present in insufficient quantities at the cell surface. Regardless of the specific mutation, the cellular defect in cystic fibrosis directly arises from this genetic error.
Consequences of Impaired CFTR Function in Cells
When the CFTR protein is defective or absent, its ability to transport chloride ions across cell membranes is compromised. This impaired chloride transport disrupts the normal movement of water, which typically follows chloride ions by osmosis to maintain fluid balance. Consequently, cellular surfaces become dehydrated.
This cellular dehydration leads to thick, sticky secretions, such as mucus, on cell surfaces. In the airways, for instance, this thick mucus depletes the airway surface liquid, a thin layer of fluid that allows cilia (tiny hair-like structures) to effectively clear foreign particles and pathogens. The reduced fluid layer causes the cilia to become trapped in the viscous mucus, hindering their movement and impairing mucociliary clearance.
Defective CFTR also impacts other ion channels, notably increasing the activity of epithelial sodium channels (ENaC). Normally, CFTR inhibits ENaC, but without functional CFTR, sodium ions are excessively absorbed from the cell surface into the cell. This increased sodium absorption further exacerbates the dehydration of extracellular fluids, contributing to the thick, sticky nature of secretions. The overall disruption of ion and water homeostasis at the cellular level is a fundamental characteristic of cystic fibrosis.
Multisystemic Cellular Impact
The cellular dysfunction originating from defective CFTR has widespread effects across multiple organ systems. The most recognized impact is on the lungs, where thick, sticky mucus obstructs airways. This obstruction traps bacteria, leading to frequent and chronic lung infections, inflammation, and progressive lung damage. The accumulation of viscous mucus impairs the lung’s natural defense mechanisms, making it difficult to clear pathogens.
In the pancreas, thick secretions block the ducts that release digestive enzymes into the intestines. This blockage prevents proper digestion and absorption of nutrients, leading to malnutrition and poor growth. Over time, this can result in damage to the pancreas, including fibrosis and, in some cases, cystic fibrosis-related diabetes due to impaired insulin production.
The cellular malfunction also affects sweat glands, where defective CFTR protein prevents reabsorption of chloride from sweat. This leads to unusually salty sweat, a common diagnostic indicator of the condition. Other organs, including the liver, intestines, and male reproductive tract, can also be affected by the thick secretions, demonstrating how the widespread cellular problem translates into diverse clinical manifestations of cystic fibrosis.