CF Module- Scott

Question 1

How is CF inherited?

Answer 1

Autosomal Recessive

Question 2

What gene is mutated in CF?

Answer 2

CFTR gene = cystic fibrosis transmembrane conductance regulator gene

Question 3

What does the CFTR gene code for?

Answer 3

It is a chloride and bicarb channel found on apical surface of epithelial cells lining airways, pancreatic ducts, intestines, and other tissues

Question 4

What causes 90% of deaths in CF?

Answer 4

Respiratory Failure

Question 5

How many transmembrane domains does the CFTR channel have?

Answer 5

12 transmembrane domains

Question 6

What are the two regulatory sites to promote opening of the channel?

Answer 6

R domain: gets phosphorylated

Nucleotide binding domain (NBD): binds ATP

Question 7

What is the function of CFTR channel?

Answer 7

• Controls luminal ion concentration and pH

- Controls movement of H20

Question 8

Which way is Cl- moving through the CFTR channel?

Answer 8

It is moving DOWN its concentration gradient. Into the lumen (and it pulls water with it!)

Question 9

What two regulatory signals are needed to open the CFTR channel?

Answer 9

• Cyclic AMP intercellular signaling pathway activates protein kinase A which phosphorylates the R domain
• ATP that are generated bind to the NBD domains

Question 10

What chromosome is the CFTR gene found on?

Answer 10

Chromosome 7

Question 11

Does incidence of CF vary with ethnic group?

Answer 11

YES!!! Mutation based diagnostic tests are tailored to different ethnic groups

Question 12

Which classes of CFTR mutations are more severe?

Answer 12

Class 1-3

Question 13

Which classes of CFTR mutations are less severe?

Answer 13

Class 4-5

Question 14

Which mutation is seen in 70% of CF alleles/ most common?

Answer 14

Class 2! Defective protein folding activates ER quality control and degrades protein

F508del

Question 15

G524X mutation

Answer 15

Class 1 = nonsense mutation and no protein is produced

Question 16

F508del mutation

Answer 16

Class 2 = defective protein folding activates ER quality control and degrades protein

*seen in 70% of CF alleles

Question 17

G551D mutation

Answer 17

Class 3 = defective gating or regulation of channel opening

Question 18

Describe Class 4 and 5 mutaitons

Answer 18

Class 4 = defective ion transport

Class 5= normal CFTR produced but decreased amounts

**These mutations have less severe disease

Question 19

How much CFTR activity is remaining in severe disease? (Class mutation 1-3) vs. Less Severe disease?

Answer 19

Less than 1% CFTR activity in class 1-3

Around 5% CFTR activity in class 3-4

Question 20

What are the 4 bacterial infections characteristic of CF?

Answer 20

Staph Aureus
Pseudomonas aeruginosa
Burkholderia Cepacia
H. influenza

Question 21

Describe the pathogenesis of CF

Answer 21

• Decreased ASL layer
• Build up of viscous mucous and failure to clear bacteria
• Persistent colonization and desicated mucous leads to inflammation (damaging agents)
• Infection + inflammation + mucus plugging = long term structural damage
• Ultimate outcome is respiratory failure

Question 22

Which inflammatory pathway is activated in epithelial cells?

Answer 22

LPS
LTR4
MyD88
NFkB

Question 23

What are the main inflammatory mediators in CF?

Answer 23

IL1B
TNF alpha
IL-8

*These recruit neutrophils!

Question 24

What do neutrophils release that ultimately causes damage to CFTR itself and epithelial cells?

Answer 24

Neutrophils release elastase

Question 25

What infections appears in 40-60% of pediatric patients with CF?

Answer 25

Pseudomonas Aurgenosa

Question 26

What are 4 things that help prevent pulmonary damage in pts with CF?

Answer 26

• Chest physiotherapy to improve drainage
• Aggressive treatment of infections with antibiotics
• Hypertonic Saline w/ DNAase aerosols to make mucous less viscous
• Anti-inflammatories

Question 27

When is associated liver disease considered clinically significant?

Answer 27

When it occurs with cirrhosis or portal hypertension

Question 28

How is molecular genetic knowledge used for better testing and treatment?

Answer 28

• Widespread screening

- New treatments to correct specific mutation defects

Question 29

What is the overall CF risk?

Answer 29

1/2500

Question 30

What is the definitive test for diagnosising CF?

Answer 30

The sweat test

Question 31

What is the difference in pancreatic involvement the severe (I, II, III) and less severe (IV, V) mutations?

Answer 31

The severe mutations cause a defect in pancreatic ducts. The less severe ones do not-the pancreas is sufficient!