Inherited mutations in CFTR and personalised cystic fibrosis therapy Flashcards
When was cystic fibrosis first described?
in 1930s
What does the name cystic fibrosis refer to ?
refers to scarring and cysts in the pancreas
How is cystic fibrosis often first detected?
by presence of salty skin/sweat due to increase in ionic content of sweat
What tissues are affects in CF?
many tissues are affected and mainly secretory epithelia and exocrine glands
What is the major problem with CF?
major problem with the lungs: regular infection, breathing difficulties- mainly only the lung infections are treated
- symptoms treated, not the underlying cause
What type of disorder is CF?
it is a recessive genetic disorder
- it is a more prevalent type of recessive genetic disorder
When was the CFTR gene discovered?
identified in 1980s
How many caucasians carry a defective allele for CFTR and how many are affected?
1 in 25 caucasians have defective allele and 1 in 3000-4000 are affected
What does the CFTR gene encode?
it encodes a membrane protein of the ABC transporter family - homologous to other members of ABC
- nucleotide gated chloride channel, ATP hydrolysed during activation cycles - during gating cycles
- activity is dependent upon phosphorylation by PKA
How many different mutations have been identified in CF and what is a common mutation?
over 1000 different ones
- about 70% (90% in US) have the delta F508 mutation = phenylalanine deletion
What does the CFTR channel look like ?
made up of a single peptide with 2 homologous domains
- predominantly phosphorylated following activity of protein kinase A
- phosphorylation of the R domain causes enhanced activity of the anion pore
What are normal airways like ?
requires a balance between sodium and chloride ions to get correct height of pericilliary liquid
- height/volume of pericilliary liquid between the surface of epithelial cells
has to be a certain height to allow cilia to beat to remove mucus
height is determined by homeostasis of water and sodium and chloride ions
What are the airways like in betaENaC transgenic mice/CF?
Transgenic mice have an overly active ENaC to induce symptoms
in CF it is caused by a decrease in CL- channel activity which alters the balance
cilia cant move as well
GAGs, chemokines and growth factors are not gotten rid of which causes infections
CF patients have a loss of sodium and chloride balance due to a lack of cl efflux due to loss of function mutations in CFTR
What are they trying to do to improve treatments for CF?
try to develop taylor-made treatments for each individual based upon their mutation
What are class 1 mutations ?
CFTR is not fully synthesised (e/g nonsense)
- due to nucleus function
- produces a truncated protein because the mRNA produced contains a nonsense mutation
What are class 2 mutations ?
CFTR is retained in the ER (e.g. deltaf508)
- ends up being degraded by ERAD