CF Flashcards
Cystic fibrosis has what type of inheritability?
Autosomal recessive
What gene is affected in CF?
Cystic Fibrosis Transmembrane conductance Regulator (CFTR)
CFTR encodes for what protein?
Chloride ion channel
Where does CF rank on the list of life-shortening genetic diseases?
Second only to sickle cell
What organ has the most serious consequences with CF?
Lungs
Besides the lungs, what other organs are affected by CF? Other issues?
Exocrine pancreas, intestine
Sweat glands, urogenital dysfunction
Where is the CFTR gene located?
On the long arm of chromosome 7
What is the most common mutation causing CF?
F508 delta
Why is it important to know which mutation is the most likely cause?
Treatment/therapies
Diagnosis
Which ethnic group has the highest rate of CF?
Caucasians > Hispanic > African
What are the three domains of the CFTR gene/protein?
Membrane Spanning Domains (MSD)
Nucleotide Binding Domains (NBD)
Regulatory Domain (R)
What is the role of the MSDs?
Form a pore for the chloride ions
What is the role of the NBDs?
Provide binding site for ATP –> necessary for open conformation
What is the role of the R domain?
Can be phosphorylated by PKA –> necessary for open conformation
There are three more severe CFTR mutations: what causes class 1?
Nonsense mutation –> mRNA is degraded –> no protein produced
There are three more severe CFTR mutations: what causes class 2?
Defective protein folding –> activated ER quality control –> degradation of protein
There are three more severe CFTR mutations: what causes class 3?
Defective gating or regulation of channel opening
Which class does the F508delta mutation fall under?
Class 2
Besides F508delta, what are some common mutations that cause CF?
G542X (class 1) G551D (class 3...more time in closed conformation)
In the CFTR gene, where does the F508delta mutation occur? What is the effect of the mutation?
Mutation is in NBD1 –> incorrect folding –> incorrect interactions w/ other domains
What is the net cellular effect of normal CFTR?
Outflow of water…increased EC [Cl-] and inhibited ENaC
What is not maintained in the lungs due to CF?
Airway Surface Liquid (ASL)
Why is properly maintained ASL important?
Clearance of mucous…activity of cilia and hydration of mucous
What is the key clinical manifestation of CF?
Pseudomonas aeruginosa pneumonia
Besides pseudomonas aeruginosa, what other bacteria commonly cause infections in CF patients?
H. influ
Staph. a
Burkholderia cepacia
Aspergillus fummigatus
What are some treatment options for the lungs of CF patients?
Chest physiotherapy (improves drainage) Antibiotics
Also: hypertonic saline aerosol, anti-inflammatories, DNase aerosol
Which pancreatic cells express CFTR?
Epithelial cells
What can happen to the pancreas of CF patients?
Blocked duct –> retention of enzymes –> tissue destruction
Where are intestinal cells express that CFTR?
In crypts of epithelium
What can happen to the intestine of CF patients?
Failure to secrete water –> dehydration of lumen –> viscous mucous –> obstruction, inability to absorb protein/fat, susceptible to cancer
What is usually missing in male CF patients?
Vas deferens
Why is the “sweat test” definitively diagnostic of CF?
Sweat gland CFTR is the opposite of others…usually promotes uptake of Cl-
Cannot uptake NaCl –> increased salt in sweat
Who should undergo carrier screening?
All individuals planning a pregnancy
All newborns
Family members of CF patients
What drug keeps CFTR channel open longer/more often?
Ivacaftor
Which CF mutations does Ivacaftor treat?
Mostly G551D (class 3) Also keeps any available open...helping with any form of CF (including F508delta)
Which drugs promote trafficking of F508delta CFTR to the cell surface instead of degradation?
VX-809 and VX-661
Work best with Ivacaftor
What is the effect of Ataluren?
Ribosomes are less sensitive to stop codons –> correct for premature stop codon mutations–G542X CF (class 1)
