Lecture 8 - Atypical CF Flashcards
Classic CF
severe symptoms with 2 CFTR mutations
Atpical CFTR
mild symptoms
one or no CFTR mutations
thought to be due to modifier genes involved in CFTR regulation or affecting how airway cells work
Gain of function ENaC mutations
results in lower ASL as there is increased Na+ absorption
Gain of function ENac mutation hypothesis
gain of function mutations increase sodium absorption so ASL is depleted resulting in CF-like mutations
ENaC mutations
some have no effect on sodium current, therefore do not cause symptoms
some show increased sodium current with enhanced amiloride effects
2 mutations show decreased ENaC function indicating no effect or increase the ASL therefore impacting mucocilliary
ENaC mutations show that…
protein levels remains he same, therefore no change in protein number
Classic CF nasal potential different results
decreased CFTR function with increased ENaC function
Atypical CF nasal potential difference results
chloride is mildly effected, but it is ENaC with the most effect
Isotenolol in nasal potential difference experiments
used to stimulate chloride handling
aQ493R mutation
EC loop
increased ENaC currents
massively increased current in absence of amiloride
from sodium self inhibition
Sodium feedback inhibition
Works to promote ENaC endocytosis, sodium enters cell to increase the IC conc, which promotes ENaC endocytosis in normal individuals
Sodium feedback inhibition with low EC sodium
this reduces stimulation of endocytosis
Sodium feedback inhibition can be used to…
compare currents in absence and presence of sodium to give an idea of how much endocytosis is occurring
Cleaving EnaC results in
increased Po
Uncleaved ENaC channels
near silent with a low Po therefore generating smaller ENaC currents
Cleaved ENaC channels
very active with a high Po therefore generating large ENaC currents
How to determine if mutation is due to issues with ENaC cleavage
adding chymotrypsin and nearing response
WT = increased Po with no activation of near silent channels
Sodium self inhibition
Sodium entering cell blocks the channel it entered through
BV348M mutation
Gain of function which showed a bigger increase in current when amiloride was removed. Change in Po, not due to channel number
Mouse overexpression of BSCNN1b
PCL reduced compared to WT, suggests decreased mucus clearance
Results of BSCNN1b MT mice given intra-tracheal bacteria
Some individuals with CF-life symptoms but not 2 CFTR mutations
ENaC mutations observed in patients
GoF explains symptoms observed
some ENaC LoF mutations
Different mutations seem to lead to an increase in current via changes in Po
ENaC B overexpression mouse model highlights impact on the lungs and supports that some atypical CF patients have ENaC MT
All forms of Cf are either…
Loss/gain of ENaC function or loss of CFTR function
