Cystic Fibrosis Flashcards
What causes cystic fibrosis
mutations in CFTR gene - inherited disease
How many classes of functional consequences of CFTR mutations are there
6 classes
What is the result of a class I CFTR mutation
No proteins as there is a stop mutation
What is the result of a class II CFTR mutation
Protein made in ER but not processed in apical membrane
Protein is misfolded so target for degradation
What is the result of a class III CFTR mutation
Protein made and trafficked to plasma membrane
Gating mutation causing low activity
What is the result of a class IV CFTR mutation
Channel doesn’t conclude chloride and bicarbonate as the wild type
Less function
What is the result of a class V CFTR mutation
Less protein produced so overall transport of chloride reduced
What is the result of a class VI CFTR mutation
Channels are less stable - have aa shorter half life
Retrieved quicker and degraded
What classes of CFRT mutations cause pancreatic insufficiency
I, II, III
Minimal function mutations so produce aa sever disease
What classes of CFTR mutations cause pancreatic sufficiency
Class IV, V, VI
Residual function mutations therefore there is chloride transport
What can cause different severity of lung function for the same genotype of CF sufferers
Air pollution
Genetic modifiers; single nucleotide polymorphisms
How can air pollen contribute to the severity of CF in the lungs
Particulates get stuck in the gel layer that sits on top of the ciliated cells in the peri cellular layer
Why do the cilia need to be in a hydrated environment
So the mucus isn’t thick/sticky allowing the cilia to beat
What maintains the hydration of the mucus and the peri cellular layer
ENaC and CFTR - mucocilliary clearance working
How does CF predispose the patient to chest infections
There is no chloride secretion but there is still an abortive component
Dehydrates the surface
Cilia collapse and mucus becomes thick/sticky obstructing the airway
Why is the ASL pH more acidic in CF patients
Reduced HCO3 secretion into ASL + ongoing H+ secretion = acidic ASL pH
What is the consequence of a more acidic ASL on EnaC activity
Increased activity; due to increased CAP activity and decreased SPLUNC1 function
What are potentiators
CFTR modulators that increase activity (Po) of class II gating mutants
How do potentiators work
Increases the probability of gating - potentiates G551D CFTR channel activity
Give an example of a potentiator
Ivacaftor - opens channels via an ATP independent mechanism
What are correctors
CFTR modulator that promote processing of class II mutants to the plasma membrane
How do correctors work
Protect the misfolded protein form the cell mechanisms allowing them to be trafficked to the surface
Give examples of correctors
4 - phenylbutyrate and lumacaftor
What are the defects caused by the F508del mutation
Processing; no protein at apical membrane
Gating; doesn’t behave like wild type
Unstable; once rescued has a short half life
What is combination therapy
Potentiator + corrector
Orkambi and Symdeko
What is triple combination therapy
2 correctors + 1 potentiator
Elexacaftor
What CF mutation makes the apartment not eligible for drugs and why
Class I - stop mutations
There are no proteins produced so no proteins to correct
Who would benefit from non CFTR channel regulation
Everyone with CF
Independent of the CF mutation
What is non CFTR channel regulation
Using alternative Cl- channels present
Bypasses defective CFTR to restore Cl-/HCO3- and fluid transport
Or
Using inhibitors of ENaC to help reduce salt and fluid absorption
How does alternative Cl- channel therapy work
Targets TMEM16A when the compound acts in apical purinergic receptors to increase cytotoxic Ca2+
Produces some amino acid and fluid secretion in the CF airways
What are the downfalls of using alternative Cl- channels
Effects on fluid secretion relatively short lived
Need to activate the channel directly without involving Ca2+
How can ENaC activity be decreased
Use amiloride like drugs a
Target ENaC regulation
What are the downfalls of decreasing ENaC activity
Can affect kidney functions and potassium levels
How do read through agents for class I works
Trick ribosome into not seeing the stop mutation and carry on reading the frame
No premature termination mutation
Why do read through agents have no effect on ppEV1
The mRNA produced can be broken down in nonsense mediated decays as the mRNA is still seen as incorrect
