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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?

Homozygous deltaF508
(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?



What does N6022 do?

new class of compounds; shown to increase the amount of CFTR that reaches the cell membrane and to stabilize CFTR so that its function can be important; increase levels of an important signaling molecule - S-nitrosoglutathione (GSNO(