CF

Question 1

Cystic fibrosis has what type of inheritability?

Answer 1

Autosomal recessive

Question 2

What gene is affected in CF?

Answer 2

Cystic Fibrosis Transmembrane conductance Regulator (CFTR)

Question 3

CFTR encodes for what protein?

Answer 3

Chloride ion channel

Question 4

Where does CF rank on the list of life-shortening genetic diseases?

Answer 4

Second only to sickle cell

Question 5

What organ has the most serious consequences with CF?

Answer 5

Lungs

Question 6

Besides the lungs, what other organs are affected by CF? Other issues?

Answer 6

Exocrine pancreas, intestine

Sweat glands, urogenital dysfunction

Question 7

Where is the CFTR gene located?

Answer 7

On the long arm of chromosome 7

Question 8

What is the most common mutation causing CF?

Answer 8

F508 delta

Question 9

Why is it important to know which mutation is the most likely cause?

Answer 9

Treatment/therapies

Diagnosis

Question 10

Which ethnic group has the highest rate of CF?

Answer 10

Caucasians > Hispanic > African

Question 11

What are the three domains of the CFTR gene/protein?

Answer 11

Membrane Spanning Domains (MSD)
Nucleotide Binding Domains (NBD)
Regulatory Domain (R)

Question 12

What is the role of the MSDs?

Answer 12

Form a pore for the chloride ions

Question 13

What is the role of the NBDs?

Answer 13

Provide binding site for ATP –> necessary for open conformation

Question 14

What is the role of the R domain?

Answer 14

Can be phosphorylated by PKA –> necessary for open conformation

Question 15

There are three more severe CFTR mutations: what causes class 1?

Answer 15

Nonsense mutation –> mRNA is degraded –> no protein produced

Question 16

There are three more severe CFTR mutations: what causes class 2?

Answer 16

Defective protein folding –> activated ER quality control –> degradation of protein

Question 17

There are three more severe CFTR mutations: what causes class 3?

Answer 17

Defective gating or regulation of channel opening

Question 18

Which class does the F508delta mutation fall under?

Answer 18

Class 2

Question 19

Besides F508delta, what are some common mutations that cause CF?

Answer 19

G542X (class 1)
G551D (class 3...more time in closed conformation)

Question 20

In the CFTR gene, where does the F508delta mutation occur? What is the effect of the mutation?

Answer 20

Mutation is in NBD1 –> incorrect folding –> incorrect interactions w/ other domains

Question 21

What is the net cellular effect of normal CFTR?

Answer 21

Outflow of water…increased EC [Cl-] and inhibited ENaC

Question 22

What is not maintained in the lungs due to CF?

Answer 22

Airway Surface Liquid (ASL)

Question 23

Why is properly maintained ASL important?

Answer 23

Clearance of mucous…activity of cilia and hydration of mucous

Question 24

What is the key clinical manifestation of CF?

Answer 24

Pseudomonas aeruginosa pneumonia

Question 25

Besides pseudomonas aeruginosa, what other bacteria commonly cause infections in CF patients?

Answer 25

H. influ Staph. a Burkholderia cepacia Aspergillus fummigatus

Question 26

What are some treatment options for the lungs of CF patients?

Answer 26

``` Chest physiotherapy (improves drainage) Antibiotics ``` Also: hypertonic saline aerosol, anti-inflammatories, DNase aerosol

Question 27

Which pancreatic cells express CFTR?

Answer 27

Epithelial cells

Question 28

What can happen to the pancreas of CF patients?

Answer 28

Blocked duct --> retention of enzymes --> tissue destruction

Question 29

Where are intestinal cells express that CFTR?

Answer 29

In crypts of epithelium

Question 30

What can happen to the intestine of CF patients?

Answer 30

Failure to secrete water --> dehydration of lumen --> viscous mucous --> obstruction, inability to absorb protein/fat, susceptible to cancer

Question 31

What is usually missing in male CF patients?

Answer 31

Vas deferens

Question 32

Why is the "sweat test" definitively diagnostic of CF?

Answer 32

Sweat gland CFTR is the opposite of others...usually promotes uptake of Cl- Cannot uptake NaCl --> increased salt in sweat

Question 33

Who should undergo carrier screening?

Answer 33

All individuals planning a pregnancy All newborns Family members of CF patients

Question 34

What drug keeps CFTR channel open longer/more often?

Answer 34

Ivacaftor

Question 35

Which CF mutations does Ivacaftor treat?

Answer 35

``` Mostly G551D (class 3) Also keeps any available open...helping with any form of CF (including F508delta) ```

Question 36

Which drugs promote trafficking of F508delta CFTR to the cell surface instead of degradation?

Answer 36

VX-809 and VX-661 Work best with Ivacaftor

Question 37

What is the effect of Ataluren?

Answer 37

Ribosomes are less sensitive to stop codons --> correct for premature stop codon mutations--G542X CF (class 1)