The delta F508del mutation represents the most frequent genetic alteration in individuals with Cystic Fibrosis (CF). This genetic change significantly impacts disease development. Understanding the nature of this mutation is foundational to comprehending its effects and the treatments designed to address them.
What is Delta F508del
The delta F508del mutation is a deletion involving three base pairs in the DNA sequence. This deletion results in the absence of the amino acid phenylalanine at position 508 within the protein. The “delta” symbol indicates this deletion, and “F508” specifies the exact location.
This mutation occurs within the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The CFTR gene provides instructions for a protein that functions as a channel, regulating the movement of chloride ions and water across cell membranes. The absence of phenylalanine at position 508 alters the CFTR protein’s structure, causing it to misfold.
Cellular Classification and Functional Impact
The delta F508del mutation is classified as a Class II mutation, indicating a defect in protein processing where the CFTR protein is improperly folded. Due to this misfolding, the cell’s internal quality control mechanisms in the endoplasmic reticulum recognize the protein as abnormal.
Consequently, the misfolded CFTR protein is degraded shortly after synthesis, preventing it from reaching the cell surface. This failure to transport means functional chloride channels are largely absent. The lack of these channels disrupts the normal balance of salt and water movement, leading to thick, sticky mucus characteristic of cystic fibrosis in organs like the lungs, pancreas, and sweat glands.
Inheritance and Global Presence
Cystic Fibrosis, caused by mutations like delta F508del, is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated gene, one from each parent, to develop the disease. Individuals inheriting only one copy of the delta F508del mutation are considered carriers and typically do not experience symptoms of CF.
The delta F508del mutation is the most common CF-causing mutation, found in approximately 70% of people with CF globally. Its prevalence is particularly high in populations of European descent, with about 90% of individuals with CF having at least one copy. For example, in the United States, about 1 in 30 white individuals are carriers of the F508del mutation.
Targeted Treatments for Delta F508del
Understanding the delta F508del mutation’s classification and cellular consequences has led to the development of targeted therapies known as CFTR modulators. These medications address the underlying protein defect. Two main types are correctors and potentiators.
Correctors, such as lumacaftor, tezacaftor, and elexacaftor, help the misfolded delta F508del protein achieve a more correct three-dimensional shape. This enables more protein to successfully traffic from the endoplasmic reticulum to the cell surface. Potentiators, like ivacaftor, enhance the function of any CFTR protein that reaches the cell surface, effectively holding the chloride channel gate open to allow more chloride to flow through.
Combination therapies, such as Trikafta (elexacaftor/tezacaftor/ivacaftor), are effective because they address both the protein’s trafficking defect and its subsequent function, leading to significant improvements for individuals with this mutation.