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Schema Name CFTR F508del for Cystic Fibrosis
Accession MS030300006.3
Gene(s) CFTR, ABC35, ABCC7, CF/MRP, TNR-CFTR
Schema Caption The role of F508del variant of the gene CFTR contributing to the Cystic Fibrosis disease mechanism.
Schema Description The CFTR gene is located on chromosome 7q31.2 spanning ~200kb of genomic DNA. The protein is 1480 amino acid long comprising 27 exons. Cystic Fibrosis (CF) is a monogenic disease with an autosomal recessive inheritance pattern. There are about 2000 CFTR gene mutations reported to date, though the majority are rare and not all are CF causing. There are six different traditional class of mutations (pmid: 27656143 ). CFTR F508del (p.Phe508del) is a class II 'trafficking mutation', where at best, only negligible amounts of the CFTR protein reach the apical membrane. The major characteristic of F508del is the incomplete folding of the protein caused by nucleotide-binding domain 1 (NBD1) instability. But this mutation also affects channel gating (class III) and cell surface residence time (class VI). This mutation is the most common among the European and European/American populations. The CFTR protein predominantly functions as a cyclic AMP (cAMP) regulated chloride channel in epithelial cells, but it also mediates secretion of bicarbonate and smaller amounts of other anions. In CF, the predominant cause of morbidity and mortality is lung disease, but the effects on other organs also contribute significantly to overall disease burden. The present schema addresses the role of F508del CFTR mutation in lung disease, pancreatic disease, and abnormally salty sweat from sweat glands (a biomarker for the disease).
Author(s) Lindley Darden, Isaac Bronson, Lipika R. Pal, Kunal Kundu and John Moult
Curator(s) Lindley Darden
Last Modified Mon Mar 10 2025 10:40:44 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP4.1
Stage: Protein
SSP Class: Protein Conformation
Other SSP Class: Misfolded protein
Modifier: Altered
Ontology: MESH_v20210106
SSP Instance: Misfolded F508del CFTR
Confidence Score: 5
Comment: NBD1's interaction with other CFTR domains play a critical role in F508del misfolding.
For Evidence: PMID:24970227
Against Evidence:
Component ID: SSP4.2
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class: Misfolded mutatnt protein abundance
Modifier: Decreased
Ontology: PLOSTHES_v20170921
SSP Instance: Misfolded F508del CFTR at ER
Confidence Score: 5
Comment: Due to misfolding of CFTR,a major fraction of CFTR is degraded at the ER.
For Evidence: PMID:24970227
Against Evidence:
Component ID: SSP5
Stage: Protein
SSP Class: Other
Other SSP Class: Membrane residency
Modifier: Decreased
Ontology:
SSP Instance: Reduced half-life of F508del CFTR at the membrane
Confidence Score: 5
Comment: Although a minor fraction of CFTR mutant reaches the membrane, their half life is very short; protein stability is decreased.
For Evidence: PMID:25404111
Against Evidence:
Component ID: SSP6
Stage: Cell
SSP Class: Other
Other SSP Class: Osmotic gradients
Modifier: Altered
Ontology:
SSP Instance: CFTR containing epithelial and ductal cells
Confidence Score: 5
Comment: Reduced Cl- and Na+ in lumen, reduced osmotic gradient to draw water into the lumen of specifically intestinal and airway epithelial cells and ductal cells in sweat glands
For Evidence: PMID: 27714410
Against Evidence:
Component ID: SSP17
Stage: Organ
SSP Class: Other
Other SSP Class: Malnutrition
Modifier: NA
Ontology:
SSP Instance: Inadequate absorption of nutrients in GI tract
Confidence Score: 5
Comment: The resultant exocrine pancreatic insufficiency (PI) is the leading cause of maldigestion and malabsorption of fats and proteins in GI tract in CF patients
For Evidence: PMID:25053610
Against Evidence:
Component ID: SSP8
Stage: Tissue
SSP Class: Other
Other SSP Class: Airway Mucus Composition
Modifier: Altered
Ontology:
SSP Instance: Thickening of airway MUC5B MUC5AC
Confidence Score: 5
Comment: Due to the defect in mucus composition mucus will be thickened in the airways
For Evidence: PMID:22951447
Against Evidence:
Component ID: SSP7
Stage: Tissue
SSP Class: Other
Other SSP Class: Viscous, Dehydrated Fluid
Modifier: NA
Ontology:
SSP Instance: Airway lumen
Confidence Score: 5
Comment: Hyposecretion leads to decreased airway surface liquid (ASL) and to a dehydrated and thickened periciliary liquid layer
For Evidence: PMID:17524805, PMID:24685676
Against Evidence:
Component ID: SSP15
Stage: Organ
SSP Class: Other
Other SSP Class: Obstructed Organ
Modifier: NA
Ontology:
SSP Instance: Pancreatic Duct
Confidence Score: 5
Comment: Viscious fluid blocks the pancratic ductules and the enzymes are unable to make their way to the GI lumen
For Evidence: PMID:25053610
Against Evidence:
Component ID: SSP9
Stage: Organ
SSP Class: Other
Other SSP Class: Infection Risk
Modifier: Increased
Ontology:
SSP Instance: Airways
Confidence Score: 5
Comment: Chronic infection of lungs of CF patients is usually caused by Pseudomonas (70-75% of young patients)
For Evidence: PMID:15970469
Against Evidence:
Component ID: SSP10
Stage: Organ
SSP Class: Other
Other SSP Class: Inflammation
Modifier: Increased
Ontology:
SSP Instance: Airways
Confidence Score: 5
Comment: CF patients have a persistent neutrophylic inflammation
For Evidence: PMID:15970469
Against Evidence:
Component ID: SSP14
Stage: Organ
SSP Class: Other
Other SSP Class: Fluid Composition
Modifier: Altered
Ontology:
SSP Instance: Dehydrated & thickened pancratic secretions
Confidence Score: 5
Comment: Reduced chloride and bicarbonate conductance in pancreatic duct cells produces a reduction in the osmotic gradient pulling water into the ductules, and the pancreatic secretions become less hydrated and more viscous
For Evidence: PMID:25053610
Against Evidence:
Component ID: SSP11
Stage: Organ
SSP Class: Other
Other SSP Class: Increased respiratory failure risk
Modifier: Altered
Ontology:
SSP Instance: Variability in alternations n lungs
Confidence Score: 5
Comment:
For Evidence: PMID:11932230
Against Evidence:
Component ID: SSP22
Stage: Organ
SSP Class: Other
Other SSP Class: Viscous Mucus
Modifier: NA
Ontology:
SSP Instance: Kidneys, reproductive tracts, bile duct, and salivary glands
Confidence Score: 5
Comment:
For Evidence: PMID:27714410
Against Evidence:
Component ID: SSP19
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES_v20170921
SSP Instance: Pancreatic enzymes in pancreas
Confidence Score: 5
Comment: Non-transported pancreatic enzymes accumulate in the pancreas and may be prematurely activated
For Evidence: PMID:27714410
Against Evidence:
Component ID: SSP16
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES_v20170921
SSP Instance: Pancreatic enzymes in GI lumen
Confidence Score: 5
Comment: Fewer pancreatic enzymes in the intestinal lumen
For Evidence:
Against Evidence:
Component ID: SSP20
Stage: Organ
SSP Class: Other
Other SSP Class: Tissue Damage
Modifier: NA
Ontology:
SSP Instance: Pancreatic duct
Confidence Score: 5
Comment:
For Evidence: PMID:27714410
Against Evidence:
Component ID: SSP21
Stage: Organ
SSP Class: Other
Other SSP Class: Pancreatic insufficiency risk
Modifier: Increased
Ontology:
SSP Instance: Pancreas
Confidence Score: 5
Comment:
For Evidence: PMID:27714410
Against Evidence:
Component ID: SSP1
Stage: DNA
SSP Class: IN/DEL [HOM]
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: F508del in CFTR
Confidence Score: 5
Comment: The disease causing mutations are autosomal homozygous [HOM} recessive, consisting of a three codon deletion [IN/DEL] F508del, also designated rs113993960. $0style="color: rgb(11, 31, 178); font-size: 12px; font-weight: 700; background-color: rgb(255, 208, 109);">The out-of-frame deletion of 3 nucleotides (CTT) leads to the loss of phenylalanine-508 (ΔF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC→ATT
For Evidence: PMID:24970227, PMID:25404111 , PMID:25514096
Against Evidence:
Component ID: SSP23
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease
Modifier: NA
Ontology:
SSP Instance: Cystic Fibrosis
Confidence Score: 5
Comment: The F508del mutation in CFTR affects numerous organs and has variable phenotypic expression.
For Evidence:
Against Evidence: PMID:25404111
Component ID: SSP2
Stage: RNA
SSP Class: IN/DEL
Other SSP Class:
Modifier: NA
Ontology: NCIT_v20210125
SSP Instance: Altered mRNA
Confidence Score: 5
Comment: The mutation I507-ATC→ATT SCC alters ΔF508 CFTR mRNA structure and translation dynamics.
For Evidence: PMID:23907436
Against Evidence:
Component ID: SSP12
Stage: DNA
SSP Class: Other
Other SSP Class: Modifier genes
Modifier: Increased
Ontology:
SSP Instance: Multiple genes
Confidence Score: 3
Comment: Modifier genes affect the severity of the cystic fibrosis phenotype
For Evidence: PMID:25404111 , PMID:21602797 , PMID:26417704 , PMID:19242412
Against Evidence:
Component ID: SSP3
Stage: Protein
SSP Class: IN/DEL
Other SSP Class:
Modifier: NA
Ontology: NCIT_v20210125
SSP Instance: Altered Protein sequence
Confidence Score: 5
Comment: This mutation leads to the loss of phenylalanine-508 (ΔF508)
For Evidence:
Against Evidence:
Biomarker(s) Annotations
Component ID: SSP13
Stage: Organ
SSP Class: Other
Other SSP Class: Sweat composition
Modifier: Altered
Ontology:
SSP Instance: Salty sweat
Confidence Score: 5
Comment: Salty sweat has long been a good biomarker for cystic fibrosis
For Evidence: PMID:17557942, PMID:27258095
Against Evidence:
Mechanism Module (MM) Annotations
Component ID: MM3
Mechanism Class Name:
Other Mechanism Class Name: Protein folding
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: F508 is located at NBD1 domain of the CFTR protein and deletion of this region causes impaired domain domain interaction with other domains (MSD) and loops (intracellular loop 4, ILC4) during protein folding.
For Evidence: PMID:25404111, PMID:24970227
Against Evidence:
Component ID: MM4
Mechanism Class Name: Protein Degradation Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Some of the misfolded CFTR will be degraded at the endoplasmic reticulum by ERAD process.
For Evidence: PMID:24970227, PMID:30485852
Against Evidence:
Component ID: MM5
Mechanism Class Name: Transport rate from ER to plasmamembrane
Other Mechanism Class Name:
Modifer: Decreased
Ontology:
Mechanism Instance: Decreased Transport rate from ER to plasma membrane
Confidence Score: 5
Comment: A minor fraction of misfolded CFTR escapes the ER quality control check and is transported to the plasma membrane.
For Evidence: PMID:25404111
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: Transport Rate
Modifer: Decreased
Ontology: GO_v20210203
Mechanism Instance: Decreased Transport of chloride across epithilial cell membranes
Confidence Score: 5
Comment: The reduced number of functional chloride channels yield s reduced chloride permeability and reduced chloride transport. CFTR also transports bicarbonate which contributes to the osmotic gradient.
For Evidence: PMID:22698459
Against Evidence:
Component ID: MM14
Mechanism Class Name:
Other Mechanism Class Name: Salt reuptake from sweat
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: CFTR is a chloride transport channel. Its malfunction leads to less salt reuptake in sweat glands.
For Evidence: PMID:25404111
Against Evidence:
Component ID: MM18
Mechanism Class Name:
Other Mechanism Class Name: Enzymatic catabolism of injested fats
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Less enzymatic activity during digestion, especially of fats and fat-soluble vitamins
For Evidence: PMID:25053610
Against Evidence:
Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Water secretion from airway epithelial cells
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Osmotic gradient prevents adiquate amounts of water from being secreted into the lumen
For Evidence: PMID:24685676
Against Evidence:
Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: clearance of mucus and inhaled pathogens
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Pathogens are caught in the mucus. To prevent their poliferation, the mucus must be cleared from the airways.
For Evidence: PMID:22951447, PMID:17524805
Against Evidence:
Component ID: MM16
Mechanism Class Name:
Other Mechanism Class Name: Accumulation of viscous fluid in duct
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Deficiency of functional CFTR in CF leads to decreased ductal cell secretions of Cl−, water and HCO3 − , which also lowers pH . The concentrated secretions cause dilation and obstruction of the ducts, particularly in the presence of inactive digestive enzymes.
For Evidence: PMID:25053610
Against Evidence:
Component ID: MM15
Mechanism Class Name:
Other Mechanism Class Name: Water secretion from pancreatic duct cells
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Water is typically drawn out from the ductal cells into the pancreatic duct.
For Evidence: PMID:25053610
Against Evidence:
Component ID: MM10
Mechanism Class Name:
Other Mechanism Class Name: Production of pro-inflammatory cytokines
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Pro-inflammatory cytokines will be produced due to infection.
For Evidence: PMID:15970469
Against Evidence:
Component ID: MM11
Mechanism Class Name: Neutrophil sequestration & increased release of oxidants and enzymes
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Neutrophil sequestration & increased release of oxidants and enzymes
Confidence Score: 5
Comment: neutrophils
For Evidence:
Against Evidence: PMID:11932230
Component ID: MM20
Mechanism Class Name:
Other Mechanism Class Name: Water secretion from misc.epithelial cells
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: CFTR regulates many mechanisms in epithelial physiology
For Evidence: PMID:27714410
Against Evidence:
Component ID: MM17
Mechanism Class Name: Transport of pancreatic enzymes to the intestinal lumen
Other Mechanism Class Name:
Modifer: Decreased
Ontology:
Mechanism Instance: Decreased Transport of pancreatic enzymes to the intestinal lumen
Confidence Score: 5
Comment:
For Evidence: PMID:25053610
Against Evidence:
Component ID: MM19
Mechanism Class Name:
Other Mechanism Class Name: Enzyme activity on pancreatic duct cells
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence: PMID:27714410
Against Evidence:
Component ID: MM8
Mechanism Class Name: MUC5B unfolding /maturation
Other Mechanism Class Name:
Modifer: Decreased
Ontology:
Mechanism Instance: Decreased MUC5B unfolding /maturation
Confidence Score: 5
Comment: After secretion from goblet cells, MUC5B or MUC5AC dimers polymerize via N-terminal dimerization to form linear polymers. If the cell is dehydrated and there is an imbalance of Na+ ions and Cl- ions in the lumen, MUC5B cannot unfold or cannot undergo the usual maturation process from the granular form to the linear structure.
For Evidence: PMID:28352653, PMID:24685676
Against Evidence:
Component ID: MM1
Mechanism Class Name:
Other Mechanism Class Name: Transcription
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Transcription of mRNA with deletion occurs.
For Evidence:
Against Evidence:
Component ID: mm2
Mechanism Class Name:
Other Mechanism Class Name: Translation
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: The synonymous change at I507 alters the structure of F508del CFTR at the mRNA stage, which leads to a reduction in translation efficiency.
For Evidence: PMID:23907436, PMID:25404111
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM12
Comment: The actions of different modifier genes are not well understood.
For Evidence:
Against Evidence:
Component ID: MM13
Comment: How environmental factors affect phenotypic variability is not well understood.
For Evidence: PMID:25404111
Against Evidence:
Environmental Factor Annotations
Component ID: EF1
Annotation Text: Environmental Factor
Comment: Various environmental factors may influence the severity of lung alterations
For Evidence: PMID:25404111
Against Evidence:
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: Gene Therapy
Comment: Genetic reversion of the F508del variants to wild type using gene therapies of different types.
For Evidence: PMID: 25015239 , PMID: 24315439
Against Evidence:
Component ID: TT2
Annotation Text: TriKafta
Comment: The drug TRIKAFTA has three parts (elexacaftor-tezacaftor-ivacaftor ) that affect the folding and trafficking of the F508del protein to restore CFTR function underlying the cause of disease in approximately 90% of patients with cystic fibrosis.
For Evidence: PMID:31978337
Against Evidence:
Component ID: TT2
Annotation Text: TriKafta
Comment: The drug TRIKAFTA has three parts (elexacaftor-tezacaftor-ivacaftor ) that affect the folding and trafficking of the F508del protein to restore CFTR function underlying the cause of disease in approximately 90% of patients with cystic fibrosis.
For Evidence: PMID:31978337
Against Evidence:
Component ID: TT2
Annotation Text: TriKafta
Comment: The drug TRIKAFTA has three parts. Ivacaftor increases the channel opening of the F508del protein to increase Cl- transport and restore CFTR function underlying the cause of disease in approximately 90% of patients with cystic fibrosis
For Evidence: PMID:31978337
Against Evidence:
Component ID: TT5
Annotation Text: Supply enzymes
Comment: Pancreatic enzyme supplements help patients to reduce this deficiency.
For Evidence: PMID:18952504
Against Evidence:
Component ID: TT3
Annotation Text: Inhalation therapy
Comment: inhalation of hypertonic saline osmotically draws sufficient water onto CF airway surfaces to provide a clinical benefit
For Evidence: PMID:17524805
Against Evidence:
Component ID: TT4
Annotation Text: Antibiotics
Comment: Infection can be treated with antibiotics
For Evidence: PMID:18952504
Against Evidence: