Cystic Fibrosis

Question 1

Important domains of CFTR protein?

Answer 1

(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)

Question 2

What must happen before ATP is able to support channel opening?

Answer 2

(R) domain must be phosphorylated by PKA

Question 3

How do chloride channel defects affect sweat ducts and in the airway differently?

Answer 3

• 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

Question 4

Why does CF affect the lungs (airways) so badly?

Answer 4

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

Question 5

Other issues with CF?

Answer 5

(1) impaired pancreatic function

(2) meconium ileus

Question 6

What is meconium ileus?

Answer 6

an obstruction of the bowl caused by thick, abnormal meconium (meconium - dark green substance forming the first feces of a newborn infant)

Question 7

When is meconium ileus suspected?

Answer 7

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

Question 8

What is the consequence of impaired pancreatic function?

Answer 8

Lipase, amylase, proteases don’t reach intestines to digest fat, carbohydrate and protein

Question 9

Which tissues express CFTR?

Answer 9

upper airways, heart, stomach, intestine, gall bladder, uterus, testicle, epididymis, pancreas (brain, kidney and skin -> not found)

Question 10

What is the selective advantage of the Mutant CFTR gene?

Answer 10

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

Question 11

Most common genetic make-up in CF?

Answer 11

Homozygous deltaF508
(caused by protein misfolding)

Question 12

How is the CFTR mutation classified?

Answer 12

molecular and biochemical abnormalities

Question 13

Class I mutations

Answer 13

block mRNA transcription

Question 14

Class II mutations

Answer 14

prevent normal CFTR protein processing and localization

Question 15

Class III mutations

Answer 15

permit CFTR localization at the apical membrane but inhibit chloride channel conductance

Question 16

Class IV mutations

Answer 16

partial chloride channel conductance

Question 17

Class V mutations

Answer 17

affect transcription, trnslation, or protein processing resulting in reduced CFTR expression

Question 18

Which classes of CFTR mutations results in pancreatic insufficiency?

Answer 18

Class I, Class II, and Class III

Question 19

Importance of deltaF508?

Answer 19

crucial for domain-domain interaction. deltaF508 mutation prevents stabilizing interaction between NBD1 (nucleotide binding) and MSD1 (membrane spanning domain)

Question 20

What is the consequence of misfolded deltaF508?

Answer 20

Failed to be delivered to the plasma membrane

Question 21

How do drugs correct the processing of the CFTR gene in patients who disease is due to a premature nonsense mutation?

Answer 21

Read-through stop codon - which enables full-length protein to be synthesize
(available therapies - aminoglycoside antibiotis such as gentamicin, amikacin)

Question 22

What is the function of VX-809?

Answer 22

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

Question 23

What is the function of Vx-770?

Answer 23

potentiatior; designed to increase the activity of defective CFTR proteins at the cell surface

Question 24

Other names for Vx770?

Answer 24

Ivacaftor or Kalydeco

Question 25

What mutation can you use a CFTR potentiator for?

Answer 25

G551D

Question 26

What does N6022 do?

Answer 26

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(