Lecture 8: Cystic Fibrosis: pathogenesis & patient management Flashcards Preview

BIO227- Human Genetic Disorders > Lecture 8: Cystic Fibrosis: pathogenesis & patient management > Flashcards

Flashcards in Lecture 8: Cystic Fibrosis: pathogenesis & patient management Deck (12)
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1

Describe the Overview of the CFTR protein function

• Single polypeptide chain, 1480 amino acids with array of normal functions:
– Volume (liquid ~water) absorbing (airway, distal intestine)
– Salt absorbing without volume (sweat ducts)
– Volume secretory (proximal intestine, pancreas)

2

Explain the Structure and function of CFTR protein

• Consists of five domains:
- Two (trans) membrane-spanning domains (TMD1 and TMD2) =form the chloride ion channel across the membrane + anchor into membrane
- Two nucleotide-binding domains (NBD1 and NBD2) = bind and hydrolyse ATP
 stimulate channel opening and closing
- Channel regulated by (de)phosphorylation by kinase- A-> alters interactions of the regulatory (R) domain
 Phosphorylation= open channel
 Dephosphorylation= close channel
- Clues to open and close channel
-> come from NBDs and R-> via intracellular loops (ICLs) that protrude from TMDs into cytoplasm

3

Explain the mutations of CFTR protein

- Delta F508 (most common CF-causing mutation) -> codes for first nucleotide-binding domain (NBD1)
- Deletion of F508 in NBD1 F508 -> leads to improper processing + folding + intracellular degradation of the CFTR protein by ER

- Domain-assembly defects can occur -> F508 interacts with ICL4 in TMD2
= creating a cavity + disrupting the NBD1–TMD2 interface
 critical for folding and function
- Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional








- Mutations can be identified by sequencing, assigned to a protein residue and a functional domain if possible
- The functional significance of a mutation can be assessed experimentally
- Possible methods of reverting effect of the mutation can be determined

4

Explain the effects of airway disease due to CFTR mutation

- Loss of normal CFTR function and over activity of ENaC (epithelial Na channel) cause:
1. Loss of HCO3− secretion (acidification)
2. Airway surface liquid layer (ASL) dehydration disrupts mucociliary escalator
3. ASL viscosity, mucus plugging, bacterial colonization, and neutrophil-dominated inflammation
4. Bacterial and neutrophil derived proteases degrade antiproteases and antimicrobial peptides in the CF airways
5. Compromised innate immune system

5

List and define the different classes of CFTR mutants

- class 1= premature termination of CFTR mRNA translation
- class 2= degradation in the ER
- class 3= regulatory mutants that fail to respond normally to activation function- protein present but non/partial functional
- class 4= CTFR mutants that have altered channel properties
- class 5= decreased functional CFTR synthesis or transport

6

What do you have to consider about the classes when it comes to treatment?

Have to consider different treatments for classic and non-classic CF-> target different abnormalities that are less severe for some

7

Describe the features of classical and non-classical CF

Classic= non-functional CFTR
- chronic sinusitis
- severe chronic bacterial infection in airways
- severe hepatobiliary disease
- pancreatic exocrine insufficiency
- meconium ileus at birth
- sweat chloride value usually between 90-110 mmol/L or 60-90 mmol/L
- obstructive azoospermia

Nonclassical= some fucntion of CFTR-> provide survival advantage
- chronic sinusitis
- chronic bacterial infection of airways-> later onset , variable
- adequate pancreatic exocrine function -> pancreatitis
- sweat chloride value between 60-90 mmol/L, sometimes < 40 mmol/L
-obstructive azoospermia

8

Explain how genotype can correlate to phenotypes

- - Variation of genotype-> provides reason for phenotypic effects of specific mutation

9

Explain how the variation of severity of CF can occur

- Mild allele-> different mutation -> heterozygosity= 2 different CF mutations from each person come together to form mild effect= non-classic
- Homozygous for 1 mutation-> strong effect= classic
- Classic alleles-> Class I-III mutations
- Mild alleles-> Class IV-V

10

Give a mutation and describe each clinical phenotype of CF and

- least affected= milder
- miler lung disease
- pancreatic insufficiency
- abnormal sweat chloride
R117H (5T)

- Mild
- mild lung disease
- pancreatic sufficiency
- equivocal sweat chloride
- R117H (7T)

- Severe
- severe lung disease
- pancreatic insufficiency
- abnormal sweat chloride
- delta F508

11

Explain how the genotype - phenotype correlation for CF can be modified

- Limited correlation between CFTR genotype +severity of lung disease
= suggests environmental and genetic modifiers

- Several candidate genes related to innate and adaptive immune response- potential pulmonary CF modifiers

- A genetic CF modifier for meconium ileus = human chromosome 19q13.2

- Phenotypic spectrum associated with CFTR mutations ranges classically defined CF
= Patients with atypical CF

- Monosymptomatic diseases: obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis
->associated with CFTR mutations + is uncharacteristic for CF

- Other gene can interfere with CF phenotype -> affect susceptibility to certain bacterial infection

12

Explain the challenges of treatment identified by pathophysiology

Lung
- High rate of sodium absorption + low rate of chloride secretion
=reduces salt and water content in mucus -> decrease in liquid surrounding cilia
- Mucus adheres to airway surface
= decreased mucus clearing
->predisposition to Staph and Pseudomonas infections
Gastrointestinal
• Pancreas
- Absence of CFTR-> limits function of chloride-bicarbonate exchanger
=Retention of pancreatic enzymes in pancreas
= Autolysis of pancreas- destruction of pancreatic tissue

• Intestine
- Decrease in water secretion
=leads to thickened mucus
= desiccated intraluminal contents and obstruction of small and large intestines

• Biliary tree
- Retention of biliary secretion and focal biliary cirrhosis (late stage of scarring (fibrosis) of the liver)
= Bile duct proliferation, chronic cholecystitis, cholelithiasis