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 | ||||||