CFTR, or to give it its full name, Cystic Fibrosis Transmembrane conductance Receptor, is an ATP-regulated, trans-membrane chloride ion transporter. Mutations of the CFTR gene affect functioning of the chloride ion channels in these cell membranes, leading to cystic fibrosis and congenital absence of the vas deferens.
CFTR functions as a cAMP activated, ATP-regulated channel that, when working properly, allows chloride ions to flow down their concentration gradient. CFTR is found spanning the membrane of epithelial cells in many organs, including the lungs, the pancreas and the digestive tract. Normally, the protein moves chloride and thiocyanate ions (with a negative charge) out of an epithelial cell to the covering mucus. As a result, positively charged sodium ions follow these chloride ions out of the cell to maintain an overall neutral charge. This increases the total electrolyte concentration in the mucus, resulting in the movement of water out of cell by osmosis.
CFTR is of major interest due to its role in Cystic Fibrosis. If an individual inherits a CFTR gene that contains damage that results in an inactive transporter, such as a deletion of phenylalanine from position 508 in the amino acid structure, they will suffer from the defective secretory systems that characterise Cystic Fibrosis.
CFTR proteins that are mutated in this way never reach their location at the cell membrane, as they are degraded shortly after they are made. The lack of CFTR leads to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed by cilia, thick mucus cannot, so it traps bacteria that give rise to chronic infections.
There is significant research focused on CFTR, focused particularly on the prevention of disease in those at risk of cystic fibrosis. Gene therapy has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy places a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed. Thus far, progression has been hampered by cells being unable to take up the DNA from the vectors used to transfer the wild-type gene. However, much progress has been made using genetically altered adenoviridae, the virus responsible for the common cold.
Additionally, small molecules that target the mutation process that leads to a significant proportion of Cystic Fibrosis cases are being researched. These molecules target mutations that lead to early STOP codons, which cause early termination of translation and hence the production of a truncated and unusable protein. Ivacaftor (Kalydeco), approved for use by the FDA in the United States in January 2012, targets the mutation G551D (glycine in position 551 is substituted with aspartic acid). Lumacaftor aims to prevent the deletion of phenylalanine at position 508.
‘Til next time…