The F508del mutation is an alteration within the human genetic code, impacting how certain proteins are formed and function. This specific genetic change is a deletion, meaning a segment of DNA is missing, which leads to a missing component in a resulting protein.
Understanding the F508del Mutation
The F508del mutation refers to the deletion of three base pairs in the genetic code, resulting in the loss of the amino acid phenylalanine at position 508 of a particular protein. This alteration is the most frequently encountered genetic change associated with cystic fibrosis (CF), accounting for approximately two-thirds of all global CF chromosomes and present in at least one copy in about 90% of individuals with CF in the UK.
Cystic fibrosis is an inherited condition with an autosomal recessive pattern. This means an individual must inherit two copies of the mutated gene, one from each parent, to develop the disease. If a person inherits only one copy of the F508del mutation, they are considered a carrier but typically do not exhibit CF symptoms.
Impact on Cellular Function
The F508del mutation directly affects the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein acts as a chloride channel, regulating the flow of chloride ions and water across cell membranes in tissues like the lungs, pancreas, and sweat glands. Proper function of this channel is necessary for maintaining the balance of salts and fluids.
When the F508del mutation is present, the CFTR protein does not fold into its correct three-dimensional shape during production in the endoplasmic reticulum. This misfolding causes the cell’s quality control mechanisms to recognize the protein as defective and prematurely degrade it. Consequently, a reduced amount of functional CFTR protein reaches the cell surface, where it is needed to facilitate chloride and water transport.
This impaired function causes the formation of thick, sticky mucus in various organs. The mucus obstructs ducts and passageways, hindering the proper functioning of affected systems.
Manifestations and Management
The accumulation of thick, sticky mucus due to the F508del mutation leads to a range of multi-system effects, with significant impacts on the lungs and digestive system. In the lungs, this mucus can block airways, making breathing difficult and creating an environment where bacteria can easily grow, leading to recurrent infections and inflammation. Individuals often experience chronic cough, sputum production, and wheezing.
The pancreas is also frequently affected, with the thick mucus blocking ducts that release digestive enzymes. This can result in pancreatic insufficiency, leading to poor nutrient absorption, fatty stools, and impaired growth. Other manifestations can include sinus infections, nasal polyps, and issues with the liver and sweat glands, where abnormal electrolyte levels can cause dehydration.
Diagnosis often begins with newborn screening tests, followed by additional blood tests or a sweat chloride test, which measures the salt level in sweat. The presence of two disease-causing CFTR mutations, such as F508del, confirms the diagnosis. Management strategies for the F508del mutation have advanced significantly with the development of CFTR modulator therapies. These medications improve the folding, processing, and function of the misfolded CFTR protein. These treatments aim to increase the amount of functional protein at the cell surface and enhance chloride transport, leading to improved lung function and a reduction in exacerbations.