Cystic Fibrosis Flashcards Preview

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Flashcards in Cystic Fibrosis Deck (21):
1

Cystic Fibrosis

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

2

Most serious consequences?

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

3

CFTR gene

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

4

Class 1 mutation

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

5

Class 2 mutation

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

6

Class 3 mutation

defective gating or regulation of channel opening
G551D, 4% of alleles

7

Class 4 mutation

defective ion transport

8

Class 5 mutation

Normal CFTR produced, but in reduced amounts

9

Severe mutations

Class 1, 2, 3
< 1% CFTR remaining --> diagnosed in first year of life

10

Least Severe mutations

Class 4, 5
5% CFTR remaining --> late presentation

11

F508del

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

12

3 most frequent mutations in US

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

13

Function of CFTR

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

14

Decreased ASL-layer

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

15

Goal of treatments?

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

16

Affects on Pancreas

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

17

Affects on Intestine

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

18

Definitive Diagnostic Test

sweat test
make patient sweat --> measure the amount of chloride in their sweat

19

Ivacaftor

treats G551D --> defective gating of channel
it corrects for it by keeping the channel in open conformation for a greater % of time

20

Ivacaftor + Lumacaftor

F508del --> defect in protein folding
it corrects for it by promoting traffic to cell surface instead of degradation

21

Ataluren

G542X --> premature stop codon
corrects for it by causing ribosome to be less sensitive to stop codons