L7 - Respiratory Channelopathies Flashcards by Jack Corston

Give an example of a respiratory channelopathy

Cystic fibrosis

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CF inheritance pattern

Autsomal recessive

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What is the main effect of CF

Alters electrolyte transport

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How many born with

1 in 2500

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How many are carriers

1 in 20

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Describe the effect on the airways

Clogging and infections

Increased incidence of persistent respiratory tract infections – symptoms multiplied

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How many experience airway effects `

Mostly all

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Effects on the liver

Blockages of the small bile ducts

Liver function problems

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How many experience liver effects

Around 5%

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Effects on the pancreas

Blockages of the ducts

Prevention of the secretion of digestive enzymes: prevents digestion of food - lack of weight being put on

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How many experience pancreas effects

Around 65%

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Effects on the small intestine

Obstruction due to thick contents - operation required for removal - then expect episodes during the life

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What percentage of newborn CF require an operation on the small intestine

10%

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Effects on the reproductive tract

Infertility in males due to absence of the Vas Deferens

Small number of issues in women

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How many male CF sufferers are infertile

95%

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Effect of CF on the skin

Excess secretion of NaCl through the sweat galnds

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What is the name for small intestine obstruction

Meconium Ileus

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How many faulty copies of the gene required for disease phenotype

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How much protein do the carriers produce

1/2

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Is half the ammount of CFTR sufficient for normal phys function

Yes

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CFTR is a ___ channel

Cl-

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Direction of the CFTR depends on

The cell type

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What does NBD stand for

Nucelotide binding domain

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How many NBDs

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What binds to the NBDs

ATP

What are the NBDs involved in

Regulation

How many CFTR transmembrane domains

What is the regulatory domain

A phosphorylation site where the ATP is hydrolysed

How many mutations are capable of causing CF

1900

70% of mutations are

Delta F508

Where is the Delta F508 mutation

NBD1

What does 'variable penetrance' mean

Genetic (non-coding) DNA and eviromental affects change the severity of the disease

Describe one environmental factor which may result in variable pentetrance

Socioeconomic | Likelyhood to take medication

Describe the effect a mutation would have on production

Protein not made

Describe the effect a mutation would have on processing

Protein is missfolded and subsequently degraded

Describe the effect a mutation would have on trafficking

Protein doesnt get to the membrane

Describe the effect a mutation would have on regulation

In NBD1/2 and R region | Channel doesnt open

Describe the effect a mutation would have on conduction

Makes it to the membrane but doesnt open

What is the most common mutation for CF

Delta F508

What is the allelic frequency of delta F508

90%

Name other mutations with a 1-3% allelic frequency

G551D W1282X GS43X N1303K

What mutation has an unusually high allelic frequency of 30% in the UK

G551D

Describe the pathology of CF in the lung

``` Viscous airway mucous Recurrent bacterial infections Antibiotic resistance Inflammation Tissue degeneration ultimaetly leading to death ```

Why might CF patients show a.biotic resistance

May/recurrent infections --> treated with antibiotics --> development of resistance

Two channels on the apical side of the membrane of the airway cell

ENaC and CFTR

Three channels on the basolateral side of the airway cell membrane

Na/K ATPase NKCC1 K+ channel

Describe the normal airway cell model

Na/K ATPase sets up a low IC Na Causes influx for Na through NKCC1 - along with K and 2 Cl K recycled through basolateral membrane Cl leaves through CFTR channel on the apical membrane Normal function of CFTR to inhibit ENaC This keeps air-fluid layer high enoguh (7 um) to keep cilia covered and allow them to beat

Describe the airway cell model for CF sufferers

Na/K ATPase sets up a low IC Na Causes influx for Na through NKCC1 - along with K and 2 Cl K recycled through basolateral membrane CFTR not present ENaC is not inhibited Water drawn in causing thickness of air-fluid layer to decrease Cilia unable to beat, and fold over

What is the evidence from bronchial cell cultures

Both started with an abnormally high air fluid layer Control can regulate thickness of layer to 7 um Experimental (CF -/-) cant regulate and air fluid layer falls very low

In the deltaF508 mutation what is normal

Production, conduction and regulation

What is abnormal about the protein in a delat F508 mutation

It misfolds so is degraded and doesn't make it the membrane

What would happen if the delta F508 mutant protein made it to the membrane

It would almost function normally

Describe why allelic frequency for CFTR is so high

CFTR present on colonic crypt cells When bacterial infection, bact produce enterotoxins, these then act of CFTR causing excess Cl secretion so excess water in the faeces --> cholera/diahhorrea In carriers only half the amount of CFTR protein, so less Cl and H20 in the faeces ==> more likely to survive a cholera infection

List some of the current treatments for CF

``` Physiotherapy Antibiotics Mucolytics (Dnase) break down mucous Bronchodilator Steroids ```

Describe how gene therapy for CF may work

Deliver CFTR DNA to the cells DNA then transcribed Functional CFTR protein produced

Which cells would be easiest to target with gene therapy

The lungs

Issues with gene therapy to treat CF

Challenging - how would you deliver the genes to other cells of the body Expensive Poor success rate

Describe how a read through agent would work

Force production of the full length protein when there may be premature stop codons or nonsense mutations

Example of a read through agen

Aminoglycoside antibiotics | e.g. gentamycin

Decribe how correctors would work

Force mutant CFTR to the membrane - if it is functional then normal phys restored

Example of a mutation where a corrector would work

Delta F508

Describe how a potentiator would work

Increase the open prob, of the CFTR (these must have been trafficked to the membrane)

Example of a potentiator

Ivacaftor VX-770

What mutation does Ivacaftor target

G551D

What combination of drugs would be good for a delta F508 mutation

Potentiators and correctors

Describe the results of the Ivacaftor clinical trials

Increase in thickness of the fluid layer Increase in the absolute change in FEV1% Proportion of event-free subjects was higher than in the placebo groups Sweat Cl conc fall to below the clinical threshold