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CFTR Mutations

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
 

Total CFTR Equation Total CFTR Equation


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
Image showing normal CFTR Protien Image showing no CFTR Protien Image showing misfolded CFTR Image showing CFTR Protein with Faulty gate Image showing inefficient CFTR Image showing reduced synthesis of CFTR Image showing degraded CFTR
  Reduces CFTR quantity Reduces CFTR function Reduces CFTR quantity
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
Image showing normal CFTR Protien Image showing no CFTR Protien Image showing misfolded CFTR Image showing CFTR Protein with Faulty gate Image showing inefficient CFTR Image showing reduced synthesis of CFTR Image showing degraded CFTR
  Reduces CFTR quantity Reduces CFTR function Reduces CFTR quantity
NormalClass I1,2,4Class II1,2,4Class III1,2,4Class IV1,2,4Class V1,2,4,7Class VI1,2,4

Mutation examples

G542X
W1282X 		F508del
N1303K 
A561E		G551D
S549R
G1349D		R117H 
R334W
A455E		3849+10kbC→T
A455E		4326delTC
CFTR defectNo 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
Image showing normal CFTR ProtienImage showing no CFTR ProtienImage showing misfolded CFTRImage showing CFTR Protein with Faulty gateImage showing inefficient CFTRImage showing reduced synthesis of CFTRImage showing degraded CFTR
 Reduces CFTR quantityReduces CFTR functionReduces 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

Conversation Considerations for Caregivers

It’s important to help caregivers understand how a patient’s CF genotype could impact their care.8 When the genotype is known, the care team can personalize treatment plans to help optimize each patient’s unique situation.12 The following discussion points are provided as examples.

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