Cystic Fibrosis

Question 1

What causes cystic fibrosis

Answer 1

mutations in CFTR gene - inherited disease

Question 2

How many classes of functional consequences of CFTR mutations are there

Answer 2

6 classes

Question 3

What is the result of a class I CFTR mutation

Answer 3

No proteins as there is a stop mutation

Question 4

What is the result of a class II CFTR mutation

Answer 4

Protein made in ER but not processed in apical membrane
Protein is misfolded so target for degradation

Question 5

What is the result of a class III CFTR mutation

Answer 5

Protein made and trafficked to plasma membrane
Gating mutation causing low activity

Question 6

What is the result of a class IV CFTR mutation

Answer 6

Channel doesn’t conclude chloride and bicarbonate as the wild type
Less function

Question 7

What is the result of a class V CFTR mutation

Answer 7

Less protein produced so overall transport of chloride reduced

Question 8

What is the result of a class VI CFTR mutation

Answer 8

Channels are less stable - have aa shorter half life
Retrieved quicker and degraded

Question 9

What classes of CFRT mutations cause pancreatic insufficiency

Answer 9

I, II, III
Minimal function mutations so produce aa sever disease

Question 10

What classes of CFTR mutations cause pancreatic sufficiency

Answer 10

Class IV, V, VI
Residual function mutations therefore there is chloride transport

Question 11

What can cause different severity of lung function for the same genotype of CF sufferers

Answer 11

Air pollution
Genetic modifiers; single nucleotide polymorphisms

Question 12

How can air pollen contribute to the severity of CF in the lungs

Answer 12

Particulates get stuck in the gel layer that sits on top of the ciliated cells in the peri cellular layer

Question 13

Why do the cilia need to be in a hydrated environment

Answer 13

So the mucus isn’t thick/sticky allowing the cilia to beat

Question 14

What maintains the hydration of the mucus and the peri cellular layer

Answer 14

ENaC and CFTR - mucocilliary clearance working

Question 15

How does CF predispose the patient to chest infections

Answer 15

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

Question 16

Why is the ASL pH more acidic in CF patients

Answer 16

Reduced HCO3 secretion into ASL + ongoing H+ secretion = acidic ASL pH

Question 17

What is the consequence of a more acidic ASL on EnaC activity

Answer 17

Increased activity; due to increased CAP activity and decreased SPLUNC1 function

Question 18

What are potentiators

Answer 18

CFTR modulators that increase activity (Po) of class II gating mutants

Question 19

How do potentiators work

Answer 19

Increases the probability of gating - potentiates G551D CFTR channel activity

Question 20

Give an example of a potentiator

Answer 20

Ivacaftor - opens channels via an ATP independent mechanism

Question 21

What are correctors

Answer 21

CFTR modulator that promote processing of class II mutants to the plasma membrane

Question 22

How do correctors work

Answer 22

Protect the misfolded protein form the cell mechanisms allowing them to be trafficked to the surface

Question 23

Give examples of correctors

Answer 23

4 - phenylbutyrate and lumacaftor

Question 24

What are the defects caused by the F508del mutation

Answer 24

Processing; no protein at apical membrane
Gating; doesn’t behave like wild type
Unstable; once rescued has a short half life

Question 25

What is combination therapy

Answer 25

Potentiator + corrector
Orkambi and Symdeko

Question 26

What is triple combination therapy

Answer 26

2 correctors + 1 potentiator
Elexacaftor

Question 27

What CF mutation makes the apartment not eligible for drugs and why

Answer 27

Class I - stop mutations
There are no proteins produced so no proteins to correct

Question 28

Who would benefit from non CFTR channel regulation

Answer 28

Everyone with CF
Independent of the CF mutation

Question 29

What is non CFTR channel regulation

Answer 29

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

Question 30

How does alternative Cl- channel therapy work

Answer 30

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

Question 31

What are the downfalls of using alternative Cl- channels

Answer 31

Effects on fluid secretion relatively short lived
Need to activate the channel directly without involving Ca2+

Question 32

How can ENaC activity be decreased

Answer 32

Use amiloride like drugs a
Target ENaC regulation

Question 33

What are the downfalls of decreasing ENaC activity

Answer 33

Can affect kidney functions and potassium levels

Question 34

How do read through agents for class I works

Answer 34

Trick ribosome into not seeing the stop mutation and carry on reading the frame
No premature termination mutation

Question 35

Why do read through agents have no effect on ppEV1

Answer 35

The mRNA produced can be broken down in nonsense mediated decays as the mRNA is still seen as incorrect