This Academy member benefit temporarily has been made public to allow all practitioners access to content that may assist in patient care during the national pandemic response. Click here for information on joining the Academy. 

Cystic Fibrosis

CF: CFTR Mutations (2019)

There are over 1,700 known mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause dysfunction in the CFTR protein. These mutations are categorized into five classes depending on where in the pathway the CFTR protein becomes ineffective. Though not exact, CFTR class can be indicative of disease severity, symptoms and complications. Treatments may be differentially effective for people with different mutation classes. 

For the purposes of this systematic review, the workgroup thought it was important to indicate the mutation classes of participants whenever possible, since this factor could be an important confounder in the relationships examined. When authors did describe mutation type, it was often according to if the participants were homozygous or heterozygous for the most common mutation: F508del (class II). In other articles, authors only describe a proxy for mutation, such as if the participant was pancreatic insufficient or on pancreatic enzyme replacement therapy. Finally, in some articles, the “type” of CF was not described and this was considered a limitation. 

Table 1. CFTR Mutation Class Description

CFTR MUTATION CLASSES
 CLASS  NORMAL  CLASS I  CLASS II  CLASS III  CLASS IV  CLASS V
 TYPE  CFTR proten allows transfer of chloride and water at cell surface  No functional CFTR is created  CFTR protein misfolds, keeping it from moving to cell surface.  Channel gate at cell surface does not open properly.  Function of the channel at cell surface is faulty.  Normal CFTR protein is created in insufficent quantities.
 PREVALENCE    22%  88%  6%  6%  6%
 MUTATION
 EXAMPLES
   G542X
 W1282X
 R553X
 'production mutations"
 F508del
 N1303K
 I507del
 "processing mutations"
 G551D
 S549N
 "gating mutations"
 D1152H
 R347P
 R117H
 "conduction mutations"
 3840+10kbC
 ->T
 2789+5g->A
 A455E
Includes some splice mutations
 POTENTIAL THERAPIES   Read-through compounds may allow production of full-length CFTR for nonsense mutations  Correctors such lumacaftor or tezacaftor help defective CFTR fold correctly  Potentiators such as ivacaftor help open the CFTR channel, and also help increase the function of normal CFTR
 Cystic Fibrosis Foundation. "Know your Mutations: A CFTR Mutation Fact Sheet". 9/17/2017