L7 - Respiratory Channelopathies Flashcards
Give an example of a respiratory channelopathy
Cystic fibrosis
CF inheritance pattern
Autsomal recessive
What is the main effect of CF
Alters electrolyte transport
How many born with
1 in 2500
How many are carriers
1 in 20
Describe the effect on the airways
Clogging and infections
Increased incidence of persistent respiratory tract infections – symptoms multiplied
How many experience airway effects `
Mostly all
Effects on the liver
Blockages of the small bile ducts
Liver function problems
How many experience liver effects
Around 5%
Effects on the pancreas
Blockages of the ducts
Prevention of the secretion of digestive enzymes: prevents digestion of food - lack of weight being put on
How many experience pancreas effects
Around 65%
Effects on the small intestine
Obstruction due to thick contents - operation required for removal - then expect episodes during the life
What percentage of newborn CF require an operation on the small intestine
10%
Effects on the reproductive tract
Infertility in males due to absence of the Vas Deferens
Small number of issues in women
How many male CF sufferers are infertile
95%
Effect of CF on the skin
Excess secretion of NaCl through the sweat galnds
What is the name for small intestine obstruction
Meconium Ileus
How many faulty copies of the gene required for disease phenotype
2
How much protein do the carriers produce
1/2
Is half the ammount of CFTR sufficient for normal phys function
Yes
CFTR is a ___ channel
Cl-
Direction of the CFTR depends on
The cell type
What does NBD stand for
Nucelotide binding domain
How many NBDs
2
What binds to the NBDs
ATP
What are the NBDs involved in
Regulation
How many CFTR transmembrane domains
12
What is the regulatory domain
A phosphorylation site where the ATP is hydrolysed
How many mutations are capable of causing CF
1900
70% of mutations are
Delta F508
Where is the Delta F508 mutation
NBD1
What does ‘variable penetrance’ mean
Genetic (non-coding) DNA and eviromental affects change the severity of the disease
Describe one environmental factor which may result in variable pentetrance
Socioeconomic
Likelyhood to take medication
Describe the effect a mutation would have on production
Protein not made
Describe the effect a mutation would have on processing
Protein is missfolded and subsequently degraded
Describe the effect a mutation would have on trafficking
Protein doesnt get to the membrane
Describe the effect a mutation would have on regulation
In NBD1/2 and R region
Channel doesnt open
Describe the effect a mutation would have on conduction
Makes it to the membrane but doesnt open
What is the most common mutation for CF
Delta F508
What is the allelic frequency of delta F508
90%
Name other mutations with a 1-3% allelic frequency
G551D
W1282X
GS43X
N1303K
What mutation has an unusually high allelic frequency of 30% in the UK
G551D
Describe the pathology of CF in the lung
Viscous airway mucous Recurrent bacterial infections Antibiotic resistance Inflammation Tissue degeneration ultimaetly leading to death
Why might CF patients show a.biotic resistance
May/recurrent infections –> treated with antibiotics –> development of resistance
Two channels on the apical side of the membrane of the airway cell
ENaC and CFTR
Three channels on the basolateral side of the airway cell membrane
Na/K ATPase
NKCC1
K+ channel
Describe the normal airway cell model
Na/K ATPase sets up a low IC Na
Causes influx for Na through NKCC1 - along with K and 2 Cl
K recycled through basolateral membrane
Cl leaves through CFTR channel on the apical membrane
Normal function of CFTR to inhibit ENaC
This keeps air-fluid layer high enoguh (7 um) to keep cilia covered and allow them to beat
Describe the airway cell model for CF sufferers
Na/K ATPase sets up a low IC Na
Causes influx for Na through NKCC1 - along with K and 2 Cl
K recycled through basolateral membrane
CFTR not present ENaC is not inhibited
Water drawn in causing thickness of air-fluid layer to decrease
Cilia unable to beat, and fold over
What is the evidence from bronchial cell cultures
Both started with an abnormally high air fluid layer
Control can regulate thickness of layer to 7 um
Experimental (CF -/-) cant regulate and air fluid layer falls very low
In the deltaF508 mutation what is normal
Production, conduction and regulation
What is abnormal about the protein in a delat F508 mutation
It misfolds so is degraded and doesn’t make it the membrane
What would happen if the delta F508 mutant protein made it to the membrane
It would almost function normally
Describe why allelic frequency for CFTR is so high
CFTR present on colonic crypt cells
When bacterial infection, bact produce enterotoxins, these then act of CFTR causing excess Cl secretion so excess water in the faeces –> cholera/diahhorrea
In carriers only half the amount of CFTR protein, so less Cl and H20 in the faeces ==> more likely to survive a cholera infection
List some of the current treatments for CF
Physiotherapy Antibiotics Mucolytics (Dnase) break down mucous Bronchodilator Steroids
Describe how gene therapy for CF may work
Deliver CFTR DNA to the cells
DNA then transcribed
Functional CFTR protein produced
Which cells would be easiest to target with gene therapy
The lungs
Issues with gene therapy to treat CF
Challenging - how would you deliver the genes to other cells of the body
Expensive
Poor success rate
Describe how a read through agent would work
Force production of the full length protein when there may be premature stop codons or nonsense mutations
Example of a read through agen
Aminoglycoside antibiotics
e.g. gentamycin
Decribe how correctors would work
Force mutant CFTR to the membrane - if it is functional then normal phys restored
Example of a mutation where a corrector would work
Delta F508
Describe how a potentiator would work
Increase the open prob, of the CFTR (these must have been trafficked to the membrane)
Example of a potentiator
Ivacaftor VX-770
What mutation does Ivacaftor target
G551D
What combination of drugs would be good for a delta F508 mutation
Potentiators and correctors
Describe the results of the Ivacaftor clinical trials
Increase in thickness of the fluid layer
Increase in the absolute change in FEV1%
Proportion of event-free subjects was higher than in the placebo groups
Sweat Cl conc fall to below the clinical threshold
