Flashcards in Cystic Fibrosis Deck (26):
Important domains of CFTR protein?
(1) 2 trans membrane domain (forms channel)
(2) 2 nucleotide binding domains (binds and hydrolyzes ATP)
(2) regulatory domain R (phosphorylation or dephosphorylation - open or close Cl- channel)
What must happen before ATP is able to support channel opening?
(R) domain must be phosphorylated by PKA
How do chloride channel defects affect sweat ducts and in the airway differently?
- In the sweat duct, a chloride channel defect causes increased chloride and sodium concentration in sweat
- In the airway, there is decreased Cl- secretion and increased Na+ and H2O re-absorption
Why does CF affect the lungs (airways) so badly?
CF patients have decreased Cl- secretion and increased Na+ and HO re-absorption whic leads to dehydration of the mucus layer coating epithelial cells, defective mucociliary action, and mucus plugging of airways
Other issues with CF?
(1) impaired pancreatic function
(2) meconium ileus
What is meconium ileus?
an obstruction of the bowl caused by thick, abnormal meconium (meconium - dark green substance forming the first feces of a newborn infant)
When is meconium ileus suspected?
Suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting
What is the consequence of impaired pancreatic function?
Lipase, amylase, proteases don't reach intestines to digest fat, carbohydrate and protein
Which tissues express CFTR?
upper airways, heart, stomach, intestine, gall bladder, uterus, testicle, epididymis, pancreas (brain, kidney and skin -> not found)
What is the selective advantage of the Mutant CFTR gene?
possible protection from cholera toxin (reduced intestinal fluid secretion in response to cholera toxin)
** Enrichment **
in the presence of cholera toxin, chloride transport into the intestinal lumen through
Most common genetic make-up in CF?
(caused by protein misfolding)
How is the CFTR mutation classified?
molecular and biochemical abnormalities
Class I mutations
block mRNA transcription
Class II mutations
prevent normal CFTR protein processing and localization
Class III mutations
permit CFTR localization at the apical membrane but inhibit chloride channel conductance
Class IV mutations
partial chloride channel conductance
Class V mutations
affect transcription, trnslation, or protein processing resulting in reduced CFTR expression
Which classes of CFTR mutations results in pancreatic insufficiency?
Class I, Class II, and Class III
Importance of deltaF508?
crucial for domain-domain interaction. deltaF508 mutation prevents stabilizing interaction between NBD1 (nucleotide binding) and MSD1 (membrane spanning domain)
What is the consequence of misfolded deltaF508?
Failed to be delivered to the plasma membrane
How do drugs correct the processing of the CFTR gene in patients who disease is due to a premature nonsense mutation?
Read-through stop codon - which enables full-length protein to be synthesize
(available therapies - aminoglycoside antibiotis such as gentamicin, amikacin)
What is the function of VX-809?
corrector; may act to restore the function of the CFTR protein; designed to increase the amount of deltaF508 FT protein on the surface of cells lining the airway
What is the function of Vx-770?
potentiatior; designed to increase the activity of defective CFTR proteins at the cell surface
Other names for Vx770?
Ivacaftor or Kalydeco
What mutation can you use a CFTR potentiator for?