What Is the CFTR Gene? Role, Mutations, and Impact

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene is a fundamental component of human genetics. Understanding this gene provides insights into how our bodies function at a cellular level and influences various bodily processes.

The CFTR Gene’s Role

The CFTR gene codes for the CFTR protein, a large protein consisting of 1,480 amino acids. This protein acts as a channel embedded within cell membranes throughout the body. Its primary function involves regulating the movement of negatively charged chloride ions, and indirectly water, across these membranes. This transport helps maintain the proper balance of salt and water in various bodily secretions.

The CFTR protein is located on human chromosome 7. It is particularly active in cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The protein’s structure includes five functional regions, or domains: two transmembrane domains, two cytoplasmic nucleotide-binding domains, and a regulatory domain.

For the channel to open and allow ion flow, the regulatory domain must be phosphorylated, and ATP must bind to the nucleotide-binding domains. When functioning correctly, this protein ensures that bodily fluids remain thin and freely flowing, which is important for roles such as lubrication and waste removal. The proper movement of chloride ions from inside the cell to the outside, known as the airway lumen, helps maintain a watery fluid layer on cell surfaces.

How CFTR Gene Mutations Cause Disease

Mutations within the CFTR gene can lead to a faulty or absent CFTR protein. Over 2,000 different mutations have been identified, disrupting the protein’s normal function by altering its production, proper folding, transport to the cell surface, or its ability to act as a channel.

The most common mutation, F508del, involves the deletion of one amino acid at position 508 in the CFTR protein. This mutation causes the CFTR protein to fold incorrectly during its formation. As a result, the misfolded protein is often recognized as defective by the cell’s quality control mechanisms and is prematurely degraded, preventing it from reaching the cell membrane to perform its function.

Other mutations can affect the CFTR protein’s stability or its ability to open and close effectively as an ion channel, even if it reaches the cell surface. When the CFTR protein is non-functional or dysfunctional, the regulated transport of chloride ions and water across cell membranes is disrupted. This leads to an imbalance in fluid movement, causing cells to produce abnormally thick and sticky mucus.

Impact of a Non-Functioning CFTR Gene

A non-functioning CFTR protein leads to the production of thick, sticky mucus, which significantly impacts multiple organ systems. This abnormal mucus obstructs passageways, particularly in the respiratory, digestive, and reproductive systems.

In the lungs, the thick mucus clogs the airways, making it difficult to breathe and promoting recurrent infections. This sticky mucus creates an environment conducive to bacterial growth, leading to chronic inflammation and progressive lung damage. Over time, this can result in conditions like bronchiectasis, where the airways become permanently widened and damaged.

The pancreas is also affected, as the thick mucus can block the ducts that carry digestive enzymes to the small intestine. Without these enzymes, the body cannot properly absorb nutrients from food, leading to issues such as poor weight gain, growth problems, and greasy, foul-smelling stools. In newborns, this blockage can manifest as intestinal obstruction. Additionally, sweat glands are impacted, resulting in abnormally salty sweat due to impaired chloride reabsorption. Liver problems and male infertility, caused by blockages in the vas deferens, can also occur.

Targeting the CFTR Gene for Treatment

Understanding the CFTR gene and its malfunctions has led to the development of targeted therapies for cystic fibrosis, moving beyond traditional symptomatic care. These modern treatments aim to address the underlying cause of the disease by improving the function of the faulty CFTR protein. CFTR modulators represent a significant advancement in this area.

CFTR modulators include different types of drugs: potentiators, correctors, and amplifiers. Potentiators help the faulty CFTR protein, if it reaches the cell surface, to open its channel more effectively, allowing better flow of chloride ions. Correctors assist misfolded CFTR proteins in achieving their correct three-dimensional shape and reaching the cell membrane. For example, correctors can help the F508del protein properly fold so it can be transported to the cell surface.

These modulators often work in combination to maximize their effect. Some therapies combine correctors to help the protein reach the cell surface with a potentiator to enhance its activity once there. While CFTR modulators have transformed the treatment landscape, gene therapy remains a promising area of research. Gene therapy aims to introduce a correct copy of the CFTR gene into a patient’s cells, allowing them to produce functional CFTR protein. This approach, while still developing, could offer a more permanent solution by addressing the genetic defect directly.

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