Samenvatting Cystic fibrosis

Cystic Fibrosis

Genetics

 Autosomal recessive gene
 Mutation in CFTR gene
 CFTR:
 Chloride channel activated by phosphorylation (cAMP activated PKA)
 Phosphorylation of R domain opens chloride channel
 2 sets of 6 trans-membrane domains
 2 ATP binding cassettes (ABC transporters)
 Fluid control:
 Epithelial sodium channel (ENaC) is a selective sodium ion channel that
reabsorbs sodium across the apical membrane
 ENaC and CFTR control airway surface liquid hydration
 Impaired CFTR leads to decreased hydration as only ENaC is functioning
 Mutations:
 Class I CFTR synthesis – frame shift or deletions
 Class II processing of CFTR – mutations leading to defective transport protein
folding
 Class III defective ion channel gate – mutations causing protein misfolding
 Class IV abnormal chloride turnover – change in CFTR structure
 Class V reduce levels of CFTR – alternative splicing or regulation

CFTR

 Thousands of possible mutations
 F508del most common
 G551D – channel isn’t regulated so closed
 R334W – chloride conduction reduced
 Delta F508:
 Phenylalanine is deleted (position 508) in ABC-1
 CFTR-DF508 has defective folding so degraded in the proteasome

Non-respiratory Pathology

 Pancreas:
 Mucous blocks exocrine ducts
 Enzymes can’t leave pancreas so proteases breakdown the tissue
 Digestive enzymes can’t escape so poor nutrition
 DM:
 Defective insulin release
 Protein catabolism causes inflammation and hyperglycaemia
 Infertility:
 Male vas deferens blocked
 Arrhythmias:
 Salt lost through excessive sweat leading to dehydration and electrolyte
imbalances




Non-Pharmacological Treatment