Cystic fibrosis transmembrane conductance regulator (CFTR) protein activity is largely determined by the quantity and function of the protein.1,2 Different CFTR mutations affect protein quantity and function in different ways.1,3
 

charts-cftr-activity charts-cftr-activity


There Are 6 Major Classes of CFTR Mutations¹

Over the years, scientists have varied on how they group these cystic fibrosis (CF)-causing gene mutations, with groupings ranging anywhere from five to seven classes.4–6 Recent literature generally breaks them into six different classes of CF-causing mutations.4 These six major classes of CFTR mutations are grouped according to their effects on CFTR protein synthesis, tracking, or function.1 The majority of identified CFTR gene mutations fall into one of these six classes.1
 

Normal Class I1,2,4 Class II1,2,4 Class III1,2,4 Class IV1,2,4 Class V1,2,4,7 Class VI1,2,4

Mutation
examples

G542X
W1282X 
F508del
N1303K 
A561E
G551D
S549R
G1349D
R117H 
R334W
A455E
3849+10kbC→T
A455E
4326delTC
CFTR defect No functional CFTR protein Mutations result in nonsense and canonical splice-site mutations, leading to complete absence of CFTR protein CFTR trafficking defect Mutations cause abnormal post-translational processing and folding of the CFTR protein, preventing correct trafficking to the cell surface Defective channel regulation Often called “gating mutations”—CFTR protein is made and reaches the cell surface, but the channel is rarely open Decreased channel conductance CFTR protein is made, localizes to the cell surface, and can open, but channel efficiency is reduced Reduced synthesis of CFTR Insufficient quantity of normal CFTR protein at the cell surface due to alternative splice mutations 

Decreased CFTR stability Reduced amount of normal functioning CFTR protein at the cell surface because of decreased stability of matured CFTR

Normal CFTR Protien No CFTR Protien Misfolded CFTR CFTR Protein with Faulty gate Inefficient CFTR mutation Degraded CFTR
  Reduces CFTR quantity Reduces CFTR function Reduces CFTR quantity

Why It’s Important for Patients and Caregivers to Know Their CF Genotype

Knowing the CF genotype can help personalize CF care.8 More than 2,000 different mutations have been identified in the CFTR gene, and different classes of mutations—depending on the extent of deficiency of CFTR protein quantity or function—can lead to variable phenotypes between different individuals.3,9 Different CFTR mutations may be classified into either high-risk or low-risk genetic groups, and therefore may help determine prognosis.10

How could patients and caregivers benefit from knowing their CF genotype?

  • They may be better able to understand their CF symptoms and how their CF may progress11
  • As different genotypes may require different treatment approaches, they are able to seek access to treatment plans that are most appropriate for them12,13
  • They can actively participate in making important decisions about their care with their doctor and healthcare team14
  • They can stay informed about research studies that may present more options for them15

Consider communicating the following points to a caregiver:

  • Two mutated CF-causing genes—one from each parent—result in CF, and together determine a person with CF’s genotype1,2
  • Different mutations impair CFTR protein function in different ways, which leads to variations in the symptoms, disease severity, and disease progression that each person with CF experiences³
  • All genotypes experience disease progression regardless of variations in presentation, making personalized disease management important throughout a patient’s lifetime¹⁶

References: 1. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013;22(127):58-65. doi:10.1183/09059180.00008412 2. Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med. 2013;1(2):158-163. doi:10.1016/S2213-2600(12)70057-7 3. Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519-2531. doi:10.1016/S0140-6736(16)00576-6 4. Amaral MD. Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients. J Intern Med. 2015;277(2):155-166. doi:10.1111/joim.12314 5. De Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016;4(8):662-674. doi:10.1016/S2213-2600(16)00023-0 6. Moskowitz SM, Chmiel JF, Sternen DL, et al. Clinical practice and genetic counseling for cystic fibrosis CFTR-related disorders. Genet Med. 2008;10(12):851-868. doi:10.1097/GIM.0b013e31818e55a2 7. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155 8. Foil KE, Powers A, Raraigh KS, Wallis K, Southern KW, Salinas D. The increasing challenge of genetic counseling for cystic fibrosis. J Cyst Fibros. 2019;18(2):167-174. doi:10.1016/j.jcf.2018.11.014 9. Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012;2(12):a009548. doi:10.1101/cshperspect.a009548 10. McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest. 2006;130(5):1441-1447. doi:10.1378/chest.130.5.1441 11. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16(1):45-56. doi:10.1038/nrg3849 12. Brodlie M, Haq IJ, Roberts K, Elborn JS. Targeted therapies to improve CFTR function in cystic fibrosis. Genome Med. 2015;7:101. doi:10.1186/s13073-015-0223-6 13. McKone EF, Velentgas P, Swenson AJ, Goss CH. Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros. 2015;14(5):580-586. doi:10.1016/j.jcf.2015.01.005 14. Mutation analysis program. Cystic Fibrosis Foundation. Accessed June 1, 2021. https://www.cff.org/Care/Clinician-Resources/Mutation-Analysis-Program 15. Clinical trial finder. Cystic Fibrosis Foundation. Accessed June 1, 2021. https://www.cff.org/Trials/Finder 16. Kapnadak SG, Dimango E, Hadjiliadis D, et al. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. J Cyst Fibros. 2020;19(3):344-354. doi:10.1016/j.jcf.2020.02.015

CFTR Mutations