Cystic Fibrosis (CF) is a genetic disorder that affects various body systems, particularly the lungs and digestive system. Individuals inherit altered genetic instructions from their parents, leading to a specific protein not functioning correctly. This malfunction results in a range of symptoms, primarily characterized by the production of unusually thick, sticky mucus.
The Normal CFTR Protein and Its Role
The CFTR, or Cystic Fibrosis Transmembrane Conductance Regulator, protein functions as an ion channel located in the cell membranes of various tissues throughout the body. Its primary role involves regulating the flow of chloride ions and water across these membranes. This precise control is necessary for maintaining the correct balance of fluids and salts on cell surfaces.
In healthy individuals, the CFTR protein ensures that mucus and other secretions remain thin and slippery. This allows them to flow freely, performing their protective and transport functions efficiently. For instance, in the airways, a properly functioning CFTR channel helps keep mucus hydrated, allowing tiny hair-like structures called cilia to clear trapped particles and bacteria. Similarly, in the pancreas, it helps produce digestive fluids with the right consistency.
The Genetic Blueprint: CFTR Gene Mutations
Cystic Fibrosis arises from specific alterations, known as mutations, within the CFTR gene. This gene provides the instructions for building the CFTR protein. These genetic changes can take several forms, including deletions where genetic material is lost, insertions where extra material is added, or point mutations that involve a single change in the DNA sequence.
One of the most frequently observed mutations is called Delta F508 (ΔF508), accounting for approximately 70% of CF cases globally. This particular mutation involves the deletion of three specific DNA building blocks, or nucleotides, from the CFTR gene. This deletion results in the absence of the amino acid phenylalanine at position 508 within the protein structure.
Hundreds of other mutations in the CFTR gene have been identified, each capable of disrupting the gene’s instructions. Some mutations might hinder the gene’s ability to produce any protein, while others might lead to the production of a protein that is malformed or unable to perform its function correctly.
From DNA Change to Abnormal Protein
The journey from a DNA change to an abnormal protein involves transcription and translation, where the genetic code is copied into messenger RNA (mRNA) and then used to build a protein. When the CFTR gene contains a mutation, this molecular blueprint is altered, leading to deviations in the resulting CFTR protein. For example, the Delta F508 mutation causes the CFTR protein to misfold shortly after creation. The cell’s quality control mechanisms recognize the protein as defective and target it for destruction, preventing it from reaching the cell surface.
Other types of mutations can have different consequences. Nonsense mutations introduce a premature stop signal in the mRNA sequence, causing translation to halt prematurely. This results in a truncated, incomplete protein that is non-functional or rapidly degraded. Mutations affecting gene splicing can lead to reduced amounts of functional mRNA, yielding less CFTR protein.
Some missense mutations, which involve a single amino acid change, might allow the CFTR protein to reach the cell surface, but its ability to transport ions is impaired. In such cases, the protein is present, but its channel function is compromised, meaning it cannot effectively regulate chloride ion flow. Each specific DNA alteration dictates a distinct flaw in the protein’s production, structure, or function.
Impact of Abnormal CFTR Protein on Cellular Function
The presence of abnormal or absent CFTR protein affects cellular function, particularly in cells lining ducts and passageways in various organs. Without functional CFTR channels, the transport of chloride ions and water across cell membranes becomes impaired. This malfunction disrupts the balance of fluids necessary for maintaining the thin, slippery consistency of mucus and other secretions.
The primary consequence is the formation of thick, sticky mucus that adheres to surfaces within the body. In the lungs, this abnormal mucus obstructs small airways, trapping bacteria and leading to persistent infections and inflammation. In the pancreas, thick secretions block ducts that deliver digestive enzymes to the small intestine, impairing nutrient absorption. Other exocrine glands, such as those producing sweat, also exhibit dysfunction, resulting in excessively salty sweat due to the inability to reabsorb chloride ions.