CFTR is a widely expressed, multifunctional protein. Its best-known function, that of a chloride channel, is responsible for the abnormal sweat test and is also responsible for some disease manifestations such as electrolyte depletion and heat exhaustion. However, it is naïve to believe that the same functions are responsible for all disease manifestations, and there is increasing evidence that dysregulation of the epithelial sodium channel ENaC is more likely responsible for the pulmonary disease. Recently, the nomenclature of CFTR gene mutations has been revised ( genetics/rmmaterials/pdf/HGVSNomenclature.pdf); however, this chapter uses the old nomenclature because it is also used in the ECFS reports. CFTR mutations have been divided into six classes (table 2): classes I–III are severe, associated with pancreatic insufficiency; classes IV–VI are mild and pancreatic sufficient. A combination of a mild and severe mutation predicts a mild (pancreatic sufficient) phenotype. However, there is considerable individual variation within genotypes, which has been related to modifications within the CFTR genetic locus itself, modifier genes elsewhere in the karyotype, and environmental factors; these are the subject of active research. Predicting prognosis in an individual from his or her genotype is not possible.

Mutation class has implications for treatment development. Whereas current therapy is aimed at the downstream consequences of CFTR dysfunction, such as bronchial infection and pancreatic destruction, treatment will in future be aimed at correcting the underlying molecular abnormality. Treatment will be either independent of mutation class (gene therapy, the efficacy of which is thought unlikely to vary with underlying CF genotype) or specific to mutation class. Examples of the latter include the orally active compound PTC124, which overrides premature but not physiological stop codons (class I mutations); molecular chaperones (‘correctors’) to prevent intracellular degradation of abnormal CFTR (class II mutations); and potentiators, to increase the activity of CFTR at the cell surface (class III mutations, but may also need to be applied to class II mutations in combination with molecular chaperones). Some of these strategies are likely to be applicable to other genetic diseases.

There are regional variations in gene frequency across Europe. In summary, homogeneity is greatest in central, western and north-eastern Europe, where 10 mutations account for more than 80% of CF chromosomes; it is much less in, for instance, Spain, Bulgaria, Turkey and Greece, where 25 mutations must be determined in order to detect 85% of CF chromosomes. This is important for a number of reasons. Firstly, if newborn screening is to be implemented, using PCR for gene detection, the panel of genes that is most useful will vary across Europe. Secondly, if a diagnostic genetics laboratory is set up, then their routine screening panel will be different in different parts of Europe. Thirdly, comparisons of survival must take account of genetic variation: countries with a higher prevalence of mild mutations (classes IV–VI) might be expected to have better survival curves than those with more severe mutations. Comparisons between countries can be facilitated by studying groups from each with the same homogeneous genotype, usually homozygous ΔF508. Finally, it should be noted that of about 1900 mutations so far identified, fewer than 50 are definitely disease producing. The ongoing CFTR-2 project should help to elucidate this, and the project website gives useful information about unusual mutations (

Class Description Example mutation
Class I No CFTR synthesis (mutation inserts premature stop codon) G542X
Class II CFTR processed incorrectly and does not reach apical cell membrane ΔF508
Class III CFTR reaches apical membrane but channel regulation is abnormal G551D
Class IV CFTR reaches apical membrane but channel open time is reduced R334W
Class V Reduced CFTR synthesis R117H
Class VI CFTR reaches apical cell membrane but has a shortened half-life due to more rapid turnover 1811+1.6kbA>G
Table 2 – Classes of cystic fibrosis transmembrane regulator (CFTR) mutation.


Adverse environmental circumstances, particularly passive and active exposure to tobacco smoke, may worsen CF, but there are no known environmental causes of the disease. However, it is estimated that environmental circumstances contribute at least as much to the prognosis as CFTR gene class and modifier genes.


Low socioeconomic status is associated with an adverse outcome at all ages. In the USA, CF patients always reliant on Medicaid (a health programme for families and individuals with a low household income) had a three-fold greater risk of dying at every age than those who never relied on Medicaid, underscoring the adverse effects of poor socioeconomic conditions.


Exceptionally rare cases of phenotypic CF with apparently completely normal CFTR gene sequences have been described. It is possible that these cases relate to mutations in one of the many genes encoding proteins with which CFTR interacts during processing, or that interact functionally with mature CFTR. Mutations in the sodium channel ENaC, which is downregulated by CFTR, have been associated with a CF-like disease.

See the entire Cystic Fibrosis Chapter