CFTR Activity and Phenotype: Both alleles contribute to total CFTR activity
Total CFTR activity, which is mainly determined by CFTR genotype, is one of a few factors that influence the phenotype of an individual and determines if he or she will develop cystic fibrosis (CF) disease and to what degree. The mutations present on both CFTR alleles determine CFTR protein production and activity.1,2
Individuals with 2 normal (wild-type) CFTR alleles produce CFTR proteins of normal quantity and function, and therefore, sufficient activity. These individuals neither have nor are carriers of CF.1,3,4
Carriers of CF have 1 normal CFTR allele, which produces normal CFTR protein, and 1 mutated CFTR allele, which produces defective CFTR protein with reduced quantity or function. In this case, there is sufficient functional CFTR protein, and hence CFTR activity, to result in a non-CF phenotype. Nonetheless, some carriers may have increased risk for certain pulmonary conditions (e.g., asthma).1,3,4
CF-causing mutations on both alleles
People who have CF-causing mutations on both alleles produce CFTR proteins that are defective in quantity or function (and sometimes both), leading to a reduction of total CFTR activity and a CF phenotype.1,2,5
The degree of reduction in total CFTR activity relates to the extent of CF manifestations. Mutations that reduce but retain some residual CFTR activity can be associated with a variation in symptoms and a spectrum of phenotypes.1-5
- Individuals with 2 normal alleles and CF carriers have the highest levels of total CFTR activity and no CF disease
- Patients with CFTR-related disorders have intermediate levels of total CFTR activity
- Patients with CF have the lowest levels of total CFTR activity
Spectrum of phenotypes associated with total CFTR activity1,3-5
CBAVD, congenital bilateral absence of the vas deferens.
CFTR mutations on both alleles contribute to the quantity of functional CFTR proteins and respective levels of total CFTR activity. CFTR mutations can result in either little to no CFTR protein activity or in residual CFTR protein activity. The extent to which the combination of CFTR alleles affects CFTR protein activity (i.e., normal, residual, little to no) influences the phenotype of an individual person.1,2,4,6
Spectrum of phenotypes associated with CFTR activity of both alleles1,4-6
Adapted from Zielenski J. Respiration. 2000;67(2):117-133.
- Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117‐133.
- Castellani C, Cuppens H, Macek M, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-196.
- Rowe SM, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane conductance regulator activity in early-phase clinical trials. Proc Am Thorac Soc. 2007;4(4):387-398.
- Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256.
- Bombieri C, Claustres M, De Boeck K, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros. 2011;10(Suppl 2). doi:10.1016/S1569-1993(11)60014-3.
- Green DM, McDougal KE, Blackman SM, et al. Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res. 2010;11(140). doi:10.1186/1465-9921-11-140.