The CFTR Protein and Gene: A Focus on Cystic Fibrosis
Introduction
Cystic fibrosis (CF) is a genetic disorder that primarily affects the lungs and digestive system, leading to severe damage. It is caused by a mutation in the cystic fibrosis transmembrane conductance (CFTR) gene. This essay aims to provide an in-depth understanding of the CFTR protein and gene, with a focus on CF.
Early History of Cystic Fibrosis
The first modern description of CF was made in 1938 by pathologist Dorothy Andersen. Based on autopsies of children who had died of malnutrition, she termed the disease “cystic fibrosis of the pancreas”. It had previously been known as “mucoviscidosis,” referring to the thickening of mucus.
In 1948, during a heat wave in New York City, pediatrician Paul di Sant’Agnese discovered a fivefold excess of sodium and chloride in the sweat of infants with CF. This discovery would lead to diagnostic tests and treatments still used today.
The CFTR Gene and Its Role in Cystic Fibrosis
The CFTR gene provides instructions for making a protein called the CF transmembrane conductance regulator (CFTR). This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged particles called chloride ions into and out of cells.
CF is caused by the presence of mutations in both copies (alleles) of the gene encoding the CFTR protein. Those with a single working copy are carriers and otherwise mostly healthy. CFTR is involved in the production of sweat, digestive fluids, and mucus. When the CFTR is not functional, secretions that are usually thin instead become thick.
The CFTR Protein and Its Structure
The CFTR protein is composed of 1,480 amino acids—the building blocks of all proteins—and is located on the surface of many cells in the body. The CFTR protein contains a single chain of amino acids that are grouped in five functional regions called domains. Two transmembrane domains (TMD1 and TMD2), two cytoplasmic nucleotide-binding domains (NBD1 and NBD2) and a regulatory domain make up the CFTR protein. Each domain has a special function when it comes to transporting chloride through the cell surface. Therefore, mutations in different domains cause a range of CF symptoms depending on the extent that chloride transport is affected.
A diagram of the CFTR Protein and its surroundings. Courtesy of continued.com
The Pathology of Cystic Fibrosis
CF affects cells that make mucus, sweat, and digestive fluids. These fluids are thick in CF patients and cause the blockage of ducts throughout the body leading to a range of symptoms. The lungs and digestive system are the main areas that are affected. Symptoms may appear soon after birth or in early childhood. In rare cases, they are not manifested until adulthood.
Conclusion
CF is a complex disease with a wide range of symptoms that can significantly impact a person’s quality of life. However, with early diagnosis and appropriate treatment, people with CF can manage their symptoms and lead fulfilling lives.
References
1: Johns Hopkins Cystic Fibrosis Center
2: NHLBI/NIH
3: Cystic Fibrosis Center
