There are over 1800 mutations of CFTR identified thus far, with 23 of them accounting for the majority of CF-causing mutations. The CF-causing mutations of CFTR can be grouped into classes depending on the physiological effect. Some mutations cause little or no protein to be made (Class I and IV), others create a defective protein that does not make it to the cell membrane (Class II), and others cannot be effectively regulated or conduct chloride (Class III and IV) (see the table below). The effect of mutations in CF leads to increased sodium reabsorption and inability to secrete chloride in the lungs, leading to desiccation of airway surface liquid and creation of thick mucus. In sweat glands, the defect leads to an inability to reabsorb chloride and sodium from the sweat ducts and therefore the sweat contains increased concentrations of these ions. Classification of the mutations allows specialized drugs to be developed to overcome the specific gene mutation. The most common mutation in CF results in a protein that lacks an amino acid, phenylalanine (Phe or F), at position 508 ( F508del). The lack of the phenylalanine affects the folding of the protein and it is trapped in the endoplasmic reticulum and degraded in the Golgi, never making it to the cell membrane.
Approximately 47% of CF patients are homozygous for the F508del mutation (ie, F508del/F508del), approximately 39% are compound heterozygotes (ie, F508del/other CF causing CFTR mutation), and about 14% have 2 non-F508del CF causing CFTR mutations. Patients who are homozygous for F508del are said to have "classical CF." Patients with classical CF tend to be pancreatic insufficient and have more severe lung disease than CF patients with other mutations.
Mutation Classes in CFTR*
|II|| Block in processing||F508del||87|
|III|| Block in gating||G551D||5|
|V|| Reduced synthesis||3849+10kbC-->T||5|
*Reference: Boyle M. Scaling the mountain: The journey to delivering transformational CF therapeutics. Available at: https://www.nacfconference.org/art/plenaryarchives/2014_Boyle.pdf
. Accessed January 2, 2015.