CF Module- Scott Flashcards
How is CF inherited?
Autosomal Recessive
What gene is mutated in CF?
CFTR gene = cystic fibrosis transmembrane conductance regulator gene
What does the CFTR gene code for?
It is a chloride and bicarb channel found on apical surface of epithelial cells lining airways, pancreatic ducts, intestines, and other tissues
What causes 90% of deaths in CF?
Respiratory Failure
How many transmembrane domains does the CFTR channel have?
12 transmembrane domains
What are the two regulatory sites to promote opening of the channel?
R domain: gets phosphorylated
Nucleotide binding domain (NBD): binds ATP
What is the function of CFTR channel?
- Controls luminal ion concentration and pH
- Controls movement of H20
Which way is Cl- moving through the CFTR channel?
It is moving DOWN its concentration gradient. Into the lumen (and it pulls water with it!)
What two regulatory signals are needed to open the CFTR channel?
- Cyclic AMP intercellular signaling pathway activates protein kinase A which phosphorylates the R domain
- ATP that are generated bind to the NBD domains
What chromosome is the CFTR gene found on?
Chromosome 7
Does incidence of CF vary with ethnic group?
YES!!! Mutation based diagnostic tests are tailored to different ethnic groups
Which classes of CFTR mutations are more severe?
Class 1-3
Which classes of CFTR mutations are less severe?
Class 4-5
Which mutation is seen in 70% of CF alleles/ most common?
Class 2! Defective protein folding activates ER quality control and degrades protein
F508del
G524X mutation
Class 1 = nonsense mutation and no protein is produced
F508del mutation
Class 2 = defective protein folding activates ER quality control and degrades protein
*seen in 70% of CF alleles
G551D mutation
Class 3 = defective gating or regulation of channel opening
Describe Class 4 and 5 mutaitons
Class 4 = defective ion transport
Class 5= normal CFTR produced but decreased amounts
**These mutations have less severe disease
How much CFTR activity is remaining in severe disease? (Class mutation 1-3) vs. Less Severe disease?
Less than 1% CFTR activity in class 1-3
Around 5% CFTR activity in class 3-4
What are the 4 bacterial infections characteristic of CF?
Staph Aureus
Pseudomonas aeruginosa
Burkholderia Cepacia
H. influenza
Describe the pathogenesis of CF
- Decreased ASL layer
- Build up of viscous mucous and failure to clear bacteria
- Persistent colonization and desicated mucous leads to inflammation (damaging agents)
- Infection + inflammation + mucus plugging = long term structural damage
- Ultimate outcome is respiratory failure
Which inflammatory pathway is activated in epithelial cells?
LPS
LTR4
MyD88
NFkB
What are the main inflammatory mediators in CF?
IL1B
TNF alpha
IL-8
*These recruit neutrophils!
What do neutrophils release that ultimately causes damage to CFTR itself and epithelial cells?
Neutrophils release elastase
What infections appears in 40-60% of pediatric patients with CF?
Pseudomonas Aurgenosa
What are 4 things that help prevent pulmonary damage in pts with CF?
- Chest physiotherapy to improve drainage
- Aggressive treatment of infections with antibiotics
- Hypertonic Saline w/ DNAase aerosols to make mucous less viscous
- Anti-inflammatories
When is associated liver disease considered clinically significant?
When it occurs with cirrhosis or portal hypertension
How is molecular genetic knowledge used for better testing and treatment?
- Widespread screening
- New treatments to correct specific mutation defects
What is the overall CF risk?
1/2500
What is the definitive test for diagnosising CF?
The sweat test
What is the difference in pancreatic involvement the severe (I, II, III) and less severe (IV, V) mutations?
The severe mutations cause a defect in pancreatic ducts. The less severe ones do not-the pancreas is sufficient!
