Cystic Fibrosis (Scott) - W4

Question 1

how is CF inherited?

Answer 1

autosomal recessive

Question 2

What is the “cause” of cystic fibrosis?

Answer 2

inactivating mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene

Question 3

What is the purpose of the CFTR ion channel?

Answer 3

Cl- and HCO3- flow OUT of cell into lumen.

promotes water movement into lumen.

Question 4

what are facts about mutations class 1 to 3

Answer 4

SEVERE.

Survival to 37 years.

pancreatin insufficiency.

at risk for diabetes and liver disease.

Question 5

What are facts about mutations 4-5

Answer 5

Less severe.

Late presentation

Survival to 50y. uncommon.

Pancreatic sufficiency.

Question 6

Class I

Answer 6

non-sense mutation creates stop codon –> no protein produced –> mRNA degraded

G542X

Question 7

Class II

Answer 7

defective protein folding in the ER –> degradation of protein

F508del

Question 8

Class III

Answer 8

defective gating and regulation of channel openings

G551D

Question 9

Class 4

Answer 9

defective in ion transport.

Question 10

Class 5

Answer 10

normal CFTR produced but decreased amounts.

Question 11

G542X

Answer 11

creates stop codon at amino acid 542 - leads to decreased mRNA and non-functional protein

Question 12

G551D

Answer 12

ion channels constnatly move between open and closed conformation - unable to respond to ATP opening signal

Question 13

F508del

Answer 13

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.

Question 14

What is the normal role of CFTR with mucociliary transport?

Answer 14

movement of cilia requires a thin layer of water. Mucous overlies this layer and provides a barrier to the bacteria.

Question 15

What is defective with cystic fibrosis involving mucous?

Answer 15

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.

Question 16

What are the immune mediators that damage the cell w/CF?

Answer 16

NKkappaB release II1B, TNFalpha and IL8 to recruit neutrophils –> these release elastase and damage the CFTR itself & the epithelium.

Question 17

What will the course of CF be without treatment?

Answer 17

Failure to clear bacteria –> inflammation –> infection + mucus plugging –> long term structural damage like bronchiolectasis and bronchectasis –> ultimate outcome is respiratory failure

Question 18

What is damaged in almost all CF patients? Why?

Answer 18

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.

Question 19

Why do those with cystic fibrosis get diabetes?

Answer 19

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.

Question 20

What can happen to the intestines with CF?

Answer 20

CFTR is normally in the crypts.

Loss of function –> failure to secrete water –> dehydration of lumen & viscous mucus in airway epithelium.

Question 21

What are consequences of dehydration of the intestinal lumen?

Answer 21

1. Obstruction - meconium ileus - newborns
   
   1. distal intestinal obsturction sydnrome - older adults
2. inability to absorb proteins, fats
3. risk of GI cancer

Question 22

What happens with CF and the liver?

Answer 22

Normally lines bile duct.

Absense lreads to retention of toxic bile acids. Excess collagen –> fibrogenesis.

Question 23

Why are males infertile with CF?

Answer 23

Vas deferens is absent

may become obstructured in fetus, or in infancy, and reabsored.

Question 24

Why can CF be detected with the sweat glands?

Answer 24

CFTR promotes uptake of Cl- ions from EC w/Na following.

Decreased absorption leads to more NaCl in sweat.

No tissue damage occurs.

Question 25

T/F. CF treatments are curative.

Answer 25

False, classic treatments are NOT currative.

Question 26

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

Answer 26

1. Widespread screening. 2. New treatments to correct specific mutation defects.

Question 27

When is prenatal testing ordered?

Answer 27

If 25% chance of having CF - both parents carriers, previous child with CF

Question 28

What is the diagnostic testing definitive test?

Answer 28

Sweat test - sweating induced by chemical treatment on skin and sweat is released over 30min is absorbed. Cl- content is measured.

Question 29

why are drug treatments feasible with CF?

Answer 29

1. must mutations have residual protein present at the cell surface. 2. A small number of mutations accounts for \>90% of the clinical disease. 3. Partial restoration of function produces clinical benefit.

Question 30

What does **ivcaftor do**? What mutation does it work with? What does it do to FEV1?

Answer 30

* 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%**

Question 31

What does **lumacaftor do**? What is it used for?

Answer 31

* corrects and promotes **traffic to the cell surface instead of degradation.** * small improvement in FEV1. * used with **F508delta.**