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Flashcards in Cystic Fibrosis Deck (21):

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


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


CFTR gene

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


Class 1 mutation

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


Class 2 mutation

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


Class 3 mutation

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


Class 4 mutation

defective ion transport


Class 5 mutation

Normal CFTR produced, but in reduced amounts


Severe mutations

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


Least Severe mutations

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



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


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


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


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


Goal of treatments?

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


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


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


Definitive Diagnostic Test

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



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


Ivacaftor + Lumacaftor

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



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