Cystic Fibrosis Flashcards
What type of mutation
How many births
How many carriers
What does it cause
Autosomal recessive
1 in 2500 births
1 in 20 is a carrier
Disease of electrolyte transport. Epithelial tissue problems.
What are the symptoms 6
Lungs- airway clogging and infection
Liver- blockage of small bile ducts and problems with liver function in 5% of cases.
Pancreas- blockage of ducts prevents secretion of digestive enzymes causing weakness and light weight in 65%
Small intestine- obstructions due to thick mucus in 10% of newborns
Reproductive tract- absence of vas deferens. 95% of males are infertile. Small number of women are too due to thicker mucus.
Skin- excess secretion of nacl via sweat glands.
When do the symptoms start to show
Small intestine problems occur first as they can’t excrete feces.
Lack of weight gain shows after a week as can’t break down milk due to pancreas problems.
Respiratory diseases begin one month in.
What symptoms do carriers have
What does the CF gene make
How many mutations in the gene are there
What is the most common
None.
Half of their proteins are abnormal but it doesn’t affect them.
A protein called cystic fibrosis transmembrane conductance regulator.
12 spanning domains.
More than 1900 that cause CF.
^F508 is 70% of mutations.
Variable penetrance
People will have the same mutations but will have different symptoms.
This is due to having different non coding regions.
And due to environmental differences.
What is the CFTR protein
Why is a symptom salty skin
A cl transporter for in and out transport.
Can be in sweat glands.
What are five types of mutation that can affect the function of CFTR
Process mutation- mutant protein is missfolded and it doesn’t get sent to the membrane and is degraded.
Production mutation- the protein is not made as the mRNA is unstable and will break down.
Trafficking mutation- protein is made correctly but is unable to be transported to the membrane.
Conduction mutation- the ion channel on the protein doesn’t work so cant transport cl.
Regulation mutation- the nucleotides and phosphorylation don’t occur correctly for the channel to open.
Common mutations
Why it’s hard to treat
F508 is 70% of cases
G55ID is 13% of UK cases
W1282X, G542X and N1303K is 1-3 %
The others are 0.1% or lower.
Lots of very rare mutations so it’s hard to treat
What problems does the mucus cause
The mucus is very thick so cannot clear infections away and this leads to recurrent bacterial infections.
They will develop antibiotic resistant bacteria in their lungs due to being given antibiotics all the time.
The infection causes inflammation which is enhanced in CF sufferers. Causing tissue degeneration which won’t grow back. This can cause poor lung function and death.
An upper airway cell and it’s mucus layer in a normal person.
There is low Na in the cell due to 3Na/2K.
The NKCC1 will allow Na, 2Cl and K to enter the cell.
The CFTR channel allows cl to leave into the mucus layer in the airways.
The secretion of cl sets the height of the mucus layer because the cl conc in the cell affects NKCC1. This will affect Na movement and Na controls where water goes. And water is in the layer.
7um is optimum.
Upper airway cell in CF
Proof
The patient can’t secrete cl into the mucus because CFTR doesn’t work.
This will make the height of the liquid layer lower than normal due to less water entry.
The lower liquid layer will cause the cillia to bend over and they can’t beat and remove mucus containing infection.
There is proof when the cells are grown in culture too.
CFTR and ENAC
Normally CFTR will inhibit ENAC
but in CF patients this doesn’t happen so there is a higher Na conc in the cells.
F508
The mutation causes trafficking problems and processing problems.
The amount of protein at the cell membrane is very low but it can function fairly well.
Treatments are being developed to get it to the membrane.
CF and the colon
CFTR in the colon helps to regulate water content
An infection will release enterotoxins and this will activate CFTR to secrete lots of cl and cause too much water secretion and diarrhoea.
Carriers of CF will have half the amount of functioning CFTR meaning cl and water secretion is halved and the change of death by dehydration is decreased.
This could explain why there are so many CF carriers because they survived cholera breakouts.
Treatments
Physiotherapy to clear mucus.
Bronchiodialators to open airways.
Antibiotics
Steroids to reduce inflammation.
Mucolytics to break mucus down.
Gene therapy- delivering CFTR DNA to target cells to make functioning proteins. But it is expensive and difficult.
