Cystic Fibrosis Flashcards
Describe the trafficking of CFTR
Under normal circumstances, the DNA is read and transcribed to messenger RNA, during which, the introns are spliced out. The messenger RNA strand exits the nucleus of the cell and travels to the ribosome, where it is translated to the immature CFTR protein product.
In the ER, chaperones help to fold the protein. CFTR is then transferred to the Golgi apparatus.
From the Golgi, transport vesicles are created and the CFTR protein is transported to the cell surface membrane.
CF is the most common inherence disease in _____.
Caucasians (30k patients in the US) and over 10million carriers
What is the most common genotype of CF?
D508- loss of the amino acid phenylalanine (other races are less likely to have this particular mutation)
What is the MOA of CF?
AR
The CFTR gene is located on the long arm of chromosome ___
7
Frequency of different CF mutations
48% F508del/F508del
39% F508del/other
13% other/other
Common ‘other’ mutations in CF?
-G542X and G551D
What is the normal function of ion/chloride channels in the airways?
Ion channels in the airway maintain the optimal height or volume of mucus (for cilia) by collectively moving salt out or in
So what is the function of CFTR?
moving chloride into the airways and down regulating ENACs, which resorb sodium
What happens when CFTR doesn’t work?
The airway surface liquid layer is reduced and the mucus dehydrated resulting impaired mucociliary clearance. The airways become obstructed with mucus and infection and inflammation soon follow resulting in lung destruction.
This occurs because CFTR is not secreting chloride and the sodium channel is absorbing too much sodium. Without salt secretion water does not move into the airway and ASL volume decreases
T or F. Mucocilliary clearance is reduced in CF
T. ASL is needed to allow cilia to beat normally and to hydrate the mucus above it for mucocilliary clearance
What is Class I CF?
result in CFTR not being synthesized at all
What mutations cause Class I CF?
1) mutation G542X: the codon for glycine (G) at position 542 is replaced with a STOP codon (X), resulting in premature termination of protein translation.
2) Frameshift mutation 394delTT: deletion of 2 T nucleotides from position 394, resulting in a frameshift during mRNA translation leading to premature termination of the protein
Can any other mutations cause Class I CF?
Splice junction mutation 1717-1GA: a nucleotide change from G to A at 1717-1, resulting in an mRNA splicing defect and failure to synthesize the protein.
What is Class II CF?
defective trafficking of CFTR to the surface.
What mutations can cause Class II CF?
Amino acid deletion ΔF508: this classic mutation involves deletion of 3 base pairs in exon 10, resulting in loss of phenylalanine (F) at position 508 (in the first nucleotide-binding domain) leading to defective processing of CFTR in the ER and, ultimately, to intracellular degradation.
What causes Class III CF?
Missense mutation G551D: glycine (G) at position 551 changes to aspartic acid (D) that block regulation of CFTR activity
What causes Class IV CF?
Missense mutation R117H: arginine (R) at position 482 changes to histidine (H) that alter conductance properties of CFTR
What causes Class V CF?
Missense mutation A455E: alanine (A) at position 455 changes to glutamic acid (E).
Alternative splicing mutation OR
3849+10kbCT: a nucleotide change from C to T in a fragment 10kB from exon 19, resulting in creation of a splice acceptor site leading to alternative mRNA splicing.
What is the result of Class V CF?
reduced synthesis of CFTR
Class I, II, and III mutations are associated with ____, whereas class IV to VI are not;
pancreatic insufficiency
class IV mutations are generally associated with a relatively mild phenotype.
What is ‘classic’ CF?
where there is no FUNCTIONAL CFTR
How does classic CF present?
- chronic sinusitis
- recurrent bacterial RT infections
- pancreatic insufficiency (hard to gain wgt without these enzymes!!)
- meconium ileus at birth
- obstructive azospermia
seen first in very young children
Sweat chloride values in classic CF?
90-110 mmol/liter
