Respiratory Channelopathies Flashcards
What type of disease is cystic fibrosis?
Autosomal recessive
What does cystic fibrosis broadly effect?
Epithelial tissues, especially in the lungs
How many people are carriers for cystic fibrosis?
1 in 20
What is the incidence of cystic fibrosis?
1 in 2,500 births
What are the impacted organs of cystic fibrosis?
The liver - 5% blocked causes liver function problems
The pancreas - 65% of blockage in ducts prevents digestion
The small intestine - 10% of newborns have a SI blockage
Reproductive tract - 95% of males with CF have no vas deferens
Skin - excess NaCl via sweat makes skin salty to taste
What are the clinical manifestations of CF from birth?
1 day to a month - meconium ileus (blockage of the SI)
1 week to 30 - pancreatic insufficiency
1 month - Distal intestinal obstruction syndrome and respiratory disorders manifest
1 - 2 years old - Liver disease manifests
3 years old - male infertility can be detected
Where is the mutation in CF?
In the cystic fibrosis transmembrane conductance regulator
How many transmembrane spanning domains does CFTR have?
12
How is CFTR opening/closing regulated
On the regulatory domain by pka phosphorylation
What are NBD1 and NBD2?
Sequences which ATP binds to
Also regulates opening and closing
How many mutations are there that can cause cystic fibrosis?
Over 1900
What is the most common mutation causing cystic fibrosis?
Changes in F508 (mutation in the NBD1 sequence
What can mutations in CFTR impact on?
Conductance - pore does not allow ions through
Regulation - Protein does not open/close properly
Trafficking - Protein does not reach the membrane
Processing - Truncated proteins, misfolding
Production - no or not enough mRNA
What is the allelic frequency of F508 mutation?
90%
What other mutations are there in the CFTR gene which have around a 1-3% allelic frequency?
G55ID
WI282x
G542x
NI303k
What is the pathology of the lungs in CF?
Viscous mucous in the airways
Recurrent bacterial infections
Inflammation - due to an immune response
Tissue degeneration
Why do patients with CF show recurrent bacterial infections?
They develop antibiotic resistance so ability to treat infections succesfully decreases over time
How do 70% of CF patients die?
Due to tissue degeneration so life is no longer sustainable
Patients have to breathe 100% oxygen near death
Where is NKCC1 located and what does it do?
On the basolateral membrane of epithelial cells, driving force for sodium influx
What is created when the CFTR channel opens?
Cl- moving out of the cell creates a driving force for sodium and water to move from the basolateral membrane to the apical membrane
What is the pelicilary layer?
A liquid layer on top of epithelial cells
Mucus sits on top of this liquid layer
Needs to be at the optimum for cilia to work properly
What is the optimum height for the pelicilary layer?
7 um
What happens if CFTR is missing in the epithelial cell model?
Sodium reabsorption by ENaC increases so the water n the pelicilary layer is pulled back so its height falls below 7um
What is ENaC usually supressed by?
CFTR
What happens if the pelicilary layer decreases below 7um?
The cilia bend over so they can’t beat properly
The patient struggles to clear mucous
What happens when the too much liquid is added to the pelicilary layer in:
a) WT
b) CFTR mutation
a) Overtimes the height of the layer falls back to normal 7um
b) The height continues to fall to about 2-3 um
What does the F508 mutation do?
Affects trafficking to the membrane of CFTR
The protein is misfolded so it is instantly degraded
If the misfolding is corrected so the CFTR can reach the membrane the CFTR works nearly as effectively as the wild type
Why is the cystic fibrosis mutation so common?
In the colon water content of faeces is determined by CFTR (Cl- secretion in the colonic crypt means water flows outwards
Cholera enterotoxins activate CFTR = diarrhoea = dehydration = death
A carrier of CF will have some protection from cholera as some water is reabsorbed, increasing the mutation frequency
What are the current treatments for the symptoms of CF?
Physiotherapy Bronchodilator drugs Antibiotics Steroids - decrease inflammation Mucolytics - break down mucus eg Dnase
Why is gene therapy for CF challenging?
Poor success rate - epithelial cells renew
Expensive to do
What are CFTR modulators?
Used to treat the cause of CF
Read through agents, correctors, potentiators or can be used in combinations
What is the impact of using a potentiator in vitro?
Very succesful against G55ID mutation - increases the height of fluid layer close to the optimum
Effective over a long term period
Reduces the likelihood of secondary problems
Sweat chloride concentrations drop below 60mmol (clinical threshold) from 100mmol
