CFTR Gene Mutations

Around 2,000 unique CFTR mutations have been described [Cystic Fibrosis Mutation Database]. However, a molecular alteration in the DNA sequence does not predict its potential effect on the expression or function of the protein product. To date, around 250 variants have evidence supporting a disease-causing effect [Castellani et al, 2008; Sosnay et al., 2013; The Clinical and Functional Translation of CFTR]. Only ~20 mutations occur at a worldwide frequency above 0.1% in patients with cystic fibrosis. Thus, determining the disease liability of very rare mutations is often difficult and requires collaborative international research [Ferec and Cutting 2012; The Clinical and Functional Translation of CFTR]. Some mutations can reach high prevalence in selected populations, due to a founder effect, in religious, ethnic or geographical isolates. 

Mutations in the CFTR gene have been grouped into six classes according to their effects on the maturation and function of the CFTR protein [Welsh and Smith, 1993; Zielenski and Tsui, 1995; Veit et al., 2016].

  • Class I mutations are nonsense mutations resulting in premature stop codons, frameshift mutations, or mRNA splicing mutations. These mutations (e.g. G542X) result in no protein production and are present in 5–10% of patients worldwide.
  • Class II mutations cause protein trafficking defects which may result in premature degradation of CFTR. The most common mutation, F508del, belongs to this class. It is present on at least one allele in 70% of patients with cystic fibrosis.
  • Class III mutations are gating mutations, allowing trafficking of CFTR to the apical membrane but causing defective regulation of the chloride channel. [Anderson 2010; Brodlie et al., 2015] They result in a very poorly-functional CFTR protein. These class III mutations are present in 4–5% of patients worldwide. The most common class III mutation is G551D and is observed in around 3% of patients worldwide (around 2,000 patients).
  • Class IV mutations, such as R117H, lead to a CFTR protein present at the apical membrane but with chloride conductance defects.
  • Class V mutations lead to the production of a normal CFTR protein but in a reduced quantity because of a limitation of transcriptional regulation. 3849+10kbC→T is an example of a Class V mutation.
  • Class VI mutations (e.g. 120del23) lead to a high turnover of CFTR at the apical surface.


This complex classification is useful but quite theoretical: some mutations occur rarely and their effect on CFTR function, and thus their class, is unknown. Similarly, some mutations may induce several CFTR protein defects belonging to different classes [Brodlie et al., 2015]. For example, the most frequent F508del mutation belongs to class II because it leads to a CFTR protein with trafficking defects, but it also belongs to class III and class VI because it presents gating defects and a high turnover when expressed at the apical cell membrane.

Class I, II and III mutations are commonly associated with pancreatic insufficiency and severe disease, whereas class IV, V and VI mutations are frequently associated with pancreatic sufficiency and a milder phenotype [McKone et al., 2003; Castellani et al., 2008]. However, it has been difficult to establish a clear relationship between CFTR genotype and lung function. Genetic modifiers and environmental factors are both thought to contribute to airway obstruction and infection with Pseudomonas aeruginosa. Other genetic modifiers have been described that may contribute to some clinical manifestations, such as CFTR-related diabetes, intestinal obstruction or nutrition. At present however, the sole focus of genetic research in the clinic is on the CFTR gene [Cutting, 2015].

Image above illustrates classification of CFTR gene mutations figure from [Derichs, 2013].

Image above illustrates classification of CFTR gene mutations figure from [Derichs, 2013].

Image above illustrates the prevalence of CFTR mutations in the United States. Data from: Cystic Fibrosis Foundation Patient Registry 2014.

Image above illustrates the prevalence of CFTR mutations in the United States. Data from: Cystic Fibrosis Foundation Patient Registry 2014.