lecture 7 - cystic fibrosis Flashcards
what is CFTR
an anion channel that controls the amount of epithelial secretions (e.g. airway surface liquid)
the most common mutation is
F508del - a loss of phenylalanine at position 508 in NBD1
class I - no protein
mutation = G542X (X represents a stop mutation)
class II - no traffic
mutation = F508del (protein is made but doesn’t process to membrane as protein is misfolded)
class III - no function
mutation = G551D (doesnt respond to normal queues that activates the channel e.g. phosphorylation) gating mutation
class IV - less function
mutation = R117H (cant conduct chloride and bicarbonate as well as the wild type)
class V - less protein
mutation = A455E (less protein produced so overall transport of chloride and bicarbonate is reduced)
class VI - less stable
mutation = rF508del (get retrieved from membrane earlier so shorter half life)
other factors affective disease
- single nucleotide polymorphisms SNPs can alter the activity and function of other genes which can modify the disease severity
- and air pollution can contribute to the severity of the lung disease
airway surface liquid is made up of
mucus layer and periciliary liquid layer (cilia in the salty solution)
proper hydration ensures efficient mucociliary clearance (MCC) which removes pathogens
in a healthy cell if theres too much fluid in ASL
ENaC is activated
in a healthy cell if there isnt enough fluid in the ASL
CFTR is activated
in CF there’s no chloride secretion but you still have sodium absorption
CFTR has a negative effect on ENaC so without CFTR, ENaC is overactive making dehydration of ASL even worse
in CF the pH of ASL is
more acidic as lack of CFTR reduces HCO3- secretion into ASL, this togethr with the proton ATPase which secretes H+ from airway cells causes more acidic ASL
consequences of more acidic pH
- increased ENaC activity - increased CAP (they cleave ENaC and increase its activity) function and decreased SPLUNC1 function
- decreased bacterial killing - reduced antimicrobial activity
- increased mucus viscosity - due to conformational changes in mucins making them more rigid
lung disease
dysfunctional CFTR -> decreased Cl and HCO3 transport -> decreased ASL volume and pH -> increased ENaC function, increases mucus obstruction, decreased MCC, decreased antimicrobial activity -> increased bacterial and viral infections, increased inflammation -> destruction of lung
treatments for CF
mucus clogging - physiotherapy and mucolytics
restore ASL - hypertonic saline (draws water from the body into airways improving hydration)
SPLUNC1 reduced in acidic pH
SPLUNC1 binds to ENaC and takes ENaC in
