Cystic Fibrosis Flashcards
(53 cards)
what is cystic fibrosis
Cystic fibrosis is an inherited disease caused by a mutation in the CFTR gene on chromsome 7, resulting in thick, viscous mucus that clogs the lungs and digestive system, causing breathing difficulties and digestion issues and leaves the person susceptible to infection
what pattern of inheritance does cystic fibrosis follow
cystic fibrosis is an autosomal recessive disorder, meaning both parents must be carriers (have one copy of mutated gene) to produce a child with cystic fibrosis
how many of UK pop are carriers
1 in 25 have one copy of the mutated CFTR gene
calculate the probability of a CF birth
probability 1 parent is a carrier= 1/25= 0.4
of 2 carriers= 0.4 x 0.4 = 1/625 families in situation
each parent has 50% chance of passing on defective copy (as have one bad, one good each) so 0.5 x 0.5= 0.25
probability of 2 carrier parents and both parents passing on defective copy instead of normal= 1/625 x 0.25= 1/2500
therefore 1 in 2500 children born with CF
what is the avg rate for CF births?
1 in 2500
CF is the most common genetic disease in what race
caucasians/ Eu descent. However, no race is exempt
being a carrier must have had a selective advantage at some point in history but we don’t know why
life expectancy CF
over 50% UK CF pop live past 41, a baby born today expected to live much longer
CF occurs when the baby inherits?
2 mutated, non functioning copies of CFTR gene
how many CFTR gene mutations are there, what is the main one
at least 2000, with 6 occurring more than 1%
F508del is the most common, 90% of CF population has
what is F508del
the deletion of a phenylaline at residue 508
what does CFTR stand for and what briefly is it
cystic fibrosis transmembrane conductance regulator
a membrane protein that functions as a chloride ion channel, found in apical epithelial cell membranes
structure of normal CFTR and how the CFTR protein works
normal CFTR has 5 conserved domains, with the 5th domain (R domain) regulating the activity of the protein.
when the 5th domain is phosphorylated, the channel can open. Phosphorylation regulates channel opening.
therefore requires binding of ATP to protein
how does CFTR normally function in the cell
CFTR allows chloride ions out of cell.
protein kinase A (eg activated by adrenaline) phosphorylates CFTR
ATP binds so channel opens
Chloride ions flow out cell, down cell conc gradient
Sodium ions follow (through different exit) to establish charge neutrality
water then diffuses out too to maintain osmoic potential
this water keeps the layer of mucus that surrounds organs hydrated
why do sodium ions follow chloride ions out
to establish charge neutrality
why does water follow sodium and chloride out
to maintain osmotic potential
how do mutations in CFTR affect its function
mutations either reduce the amount of CFTR made/available in membrance or prevent its channel activity (or both)
if chloride cannot leave the cell, sodium and water won’t follow
this means mucus layer is not hydrated
what is the effect of chloride, sodium , water being unable to leave cell (as much)
extracellular liquid layer volume is reduced so mucus becomes concentrated, its viscosity increases
as a result, mucus can’t be moved by cilia, becomes static and can obstruct airways, will be colonised by bacteria and fungi
why does F508 del affect the CFTR protein so much
F508 del destabilises the protein and it is misfolded. protein targeted for degradation by cell’s qaulity control machinery, this leads to modification of protein by ubiquitination (addition of another small protein), targets for destruction by proteosome
why is cystic fibrosis a multi organ disease
CFTR protein channels in apical membranes of epithelial cells, regulate fluid and electrolyte balance in epithelial tissues across body. therefore when dysfunction, see in:
lungs, sinuses, pancreas, intestine, repro system, sweat glands
what are the different classes of mutation in cystic fibrosis
class 1 to 5, class 1 sees no protein made, class 5 sees an unstable protein that is rapidly degraded
different classes require different treatment
why does cystic fibrosis see so much lung damage
mucus= infection
multiple infections trigger immune responses that slowly cause remodeling and fibrosis of lung tissue
why does viscous mucus in lungs cause inflammation and more infection
thick viscour mucus= cilia don’t beat mucus or trapped bacteria away
= goblet cells produce more mucus
= chronic inflammation
less sodium so more acidic, impairs bacterial killing= infection
cystic fibrosis is a state of
chronic airway inflammation
CFTR function is typically below what percent in CF patients
CFTR function below 10% in CF patients
healthy indivs and carriers 50-100%
