Cystic Fibrosis (Scott) - W4 Flashcards
how is CF inherited?
autosomal recessive
What is the “cause” of cystic fibrosis?
inactivating mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene
What is the purpose of the CFTR ion channel?
Cl- and HCO3- flow OUT of cell into lumen.
promotes water movement into lumen.
what are facts about mutations class 1 to 3
SEVERE.
Survival to 37 years.
pancreatin insufficiency.
at risk for diabetes and liver disease.
What are facts about mutations 4-5
Less severe.
Late presentation
Survival to 50y. uncommon.
Pancreatic sufficiency.
Class I
non-sense mutation creates stop codon –> no protein produced –> mRNA degraded
G542X
Class II
defective protein folding in the ER –> degradation of protein
F508del
Class III
defective gating and regulation of channel openings
G551D
Class 4
defective in ion transport.
Class 5
normal CFTR produced but decreased amounts.
G542X
creates stop codon at amino acid 542 - leads to decreased mRNA and non-functional protein
G551D
ion channels constnatly move between open and closed conformation - unable to respond to ATP opening signal
F508del
Almost a complete loss of functional protein. Incorrect folding leads to protein being retained in the ER and degraded. Doesn’t make it to the plasma membrane.
What is the normal role of CFTR with mucociliary transport?
movement of cilia requires a thin layer of water. Mucous overlies this layer and provides a barrier to the bacteria.
What is defective with cystic fibrosis involving mucous?
Mucin barrier is condensed and ineffective, so bacteria can’t be cleared from the respiratory tract. Chronic and difficult to erradicate respiratory infections can occur.
What are the immune mediators that damage the cell w/CF?
NKkappaB release II1B, TNFalpha and IL8 to recruit neutrophils –> these release elastase and damage the CFTR itself & the epithelium.
What will the course of CF be without treatment?
Failure to clear bacteria –> inflammation –> infection + mucus plugging –> long term structural damage like bronchiolectasis and bronchectasis –> ultimate outcome is respiratory failure
What is damaged in almost all CF patients? Why?
Pancreatic Duct.
Epithelial cells lining the duct express CFTR. Without it the duct is blocked by protein plugs and inflammation leads to destruction of tissues.
Why do those with cystic fibrosis get diabetes?
Pancreatic duct inflammation leads to destruction of pancreatic islet cells that make insulin.
Get similar to type I like diabetes.
Primarily due to loss of ability to make insulin.
What can happen to the intestines with CF?
CFTR is normally in the crypts.
Loss of function –> failure to secrete water –> dehydration of lumen & viscous mucus in airway epithelium.
What are consequences of dehydration of the intestinal lumen?
- Obstruction - meconium ileus - newborns
- distal intestinal obsturction sydnrome - older adults
- inability to absorb proteins, fats
- risk of GI cancer
What happens with CF and the liver?
Normally lines bile duct.
Absense lreads to retention of toxic bile acids. Excess collagen –> fibrogenesis.
Why are males infertile with CF?
Vas deferens is absent
may become obstructured in fetus, or in infancy, and reabsored.
Why can CF be detected with the sweat glands?
CFTR promotes uptake of Cl- ions from EC w/Na following.
Decreased absorption leads to more NaCl in sweat.
No tissue damage occurs.
T/F. CF treatments are curative.
False, classic treatments are NOT currative.
How is molecular gentic knowledge used for better testing and treatment?
- Widespread screening.
- New treatments to correct specific mutation defects.
When is prenatal testing ordered?
If 25% chance of having CF - both parents carriers, previous child with CF
What is the diagnostic testing definitive test?
Sweat test - sweating induced by chemical treatment on skin and sweat is released over 30min is absorbed. Cl- content is measured.
why are drug treatments feasible with CF?
- must mutations have residual protein present at the cell surface.
- A small number of mutations accounts for >90% of the clinical disease.
- Partial restoration of function produces clinical benefit.
What does ivcaftor do?
What mutation does it work with?
What does it do to FEV1?
- Keeps the CFTR ion channel open for a higher precent of the time, even without ATP gating.
- Works with G551D mutant protein.
- FEV1 increases by 10%
What does lumacaftor do?
What is it used for?
- corrects and promotes traffic to the cell surface instead of degradation.
- small improvement in FEV1.
- used with F508delta.
