Cystic Fibrosis

Question 1

Cystic Fibrosis

Answer 1

2nd most common life-shortening disease caused by genetics
Autosomal Recessive –> inactivating mutations in CFTR gene
CFTR –> chloride ion channel found on apical surface of epithelial cells

Question 2

Most serious consequences?

Answer 2

Pulmonary –> progressive lung disease is cause of death in 90% of patients
Also can get pancreas and intestine problems and male infertility

Question 3

CFTR gene

Answer 3

250,000 bp on long arm of chromo 7
Incindence varies with ethnic groups
1:28 Caucasians are carriers

Question 4

Class 1 mutation

Answer 4

no protein is produced –> nonsense mutation creates stop codon and the mRNA is degraded
G542X, 5% of alleles

Question 5

Class 2 mutation

Answer 5

defective protein folding –> activates ER quality control –> degradation of protein
F507del –> 70% of alleles (phenylalanine deletion)

Question 6

Class 3 mutation

Answer 6

defective gating or regulation of channel opening

G551D, 4% of alleles

Question 7

Class 4 mutation

Answer 7

defective ion transport

Question 8

Class 5 mutation

Answer 8

Normal CFTR produced, but in reduced amounts

Question 9

Severe mutations

Answer 9

Class 1, 2, 3

< 1% CFTR remaining –> diagnosed in first year of life

Question 10

Least Severe mutations

Answer 10

Class 4, 5

5% CFTR remaining –> late presentation

Question 11

F508del

Answer 11

principle defect in folding of protein
incorrect folding of NBD1 and incorrect interaction of NBD1 with other domains
retention of protein in ER and degradation by proteasome

Question 12

3 most frequent mutations in US

Answer 12

G542X –> creates stop codon –> decreased mRNA
G551D –> ion channel constantly moves between open and closed (great time in closed conformation)
F508del –> most common CFTR mutation!!!!!
- almost complete loss of functional protein

Question 13

Function of CFTR

Answer 13

opening and closing of CFTR controls movement of water to apical surface of epithelial cells (only move out when channel is open)
CFTR is responsible for airway surface liquid volume –> essential for clearance of mucus, activity of cilia, and hydration of mucous
- if CFTR isn’t functional, then insufficient water is delivered to surface

Question 14

Decreased ASL-layer

Answer 14

chronic airway infection and ultimately permanent damage

• build up of viscous mucous, failure to clear bacteria
• persistent colonization –> inflammation
• infection, inflammation, mucus plugging –> long-term damage

Question 15

Goal of treatments?

Answer 15

prevent pulmonary damage by limiting mucus build up and prevent or treat infections
MAINSTAYS
- chest physiotherapy –> improve drainage
- aggressive treatment of infections

Question 16

Affects on Pancreas

Answer 16

NORMAL - CFTR lines pancreatic duct –> secretes HCO3 to neutralize secretions –> water follows and prevent protein plug formation
loss of CFTR –> blockage of duct by secreted protein plugs –> damage cells –> leakage of proteolytic enzymes –> tissue destruction

Question 17

Affects on Intestine

Answer 17

CFTR expressed in crypts of intestinal epithelium
loss of function –> failure to secrete water –> dehydration of lumen and viscous mucus accumulates
results in obstruction, inability to absorb fats and proteins, susceptible to GI cancers

Question 18

Definitive Diagnostic Test

Answer 18

sweat test

make patient sweat –> measure the amount of chloride in their sweat

Question 19

Ivacaftor

Answer 19

treats G551D –> defective gating of channel

it corrects for it by keeping the channel in open conformation for a greater % of time

Question 20

Ivacaftor + Lumacaftor

Answer 20

F508del –> defect in protein folding

it corrects for it by promoting traffic to cell surface instead of degradation

Question 21

Ataluren

Answer 21

G542X –> premature stop codon

corrects for it by causing ribosome to be less sensitive to stop codons