Cystic Fibrosis (Week 2)

Autosomal recessive, pleiotropic

Cystic Fibrosis Inheritance

__ __ (pattern) and __tropic disorder - single gene mutated with wide variety of effects to different body systems

Loss, CFTR, autosomal

Pathophysiology of CF

• __ of function mutations in the __ gene

• __ recessive inheritance

Secretions, lung, pancreatic, fat, cirrhosis, male

Symptomology of CF

• Thick __ = Obstructions

• Recurrent __ infections

• __ insufficiency

• Excessive __ in stool, malnutrition, __ (liver)

• __ (male/female) infertility

Allelic heterogeneity

CFTR gene follows __ __geneity (all mutations in 1 gene)

ER, golgi, plasma membrane

• CFTR Channel is translated on __ associated with glycosylation

  • Also vesicular transport to __ and __ __

CFTR channel

ABC transporter of Cl- and HCO3-

2 transmembrane domains, one regulatory domain, 2 nucleotide-binding domains

CFTR components - (3)

Transmembrane domains

Forms the pore on CFTR channel

Regulatory domain

Phosphorylation site on CFTR channel

nucleotide-binding domains

ATP binding site, ATP hydrolysis activity

Epithelial sodium channel, HCO-/Cl- exchanger

CFTR channel interacts with__ __ __ (ENaC) and __/__ __ (SLC26 transporter)

Airway epithelium normally

• CFTR leads to Cl- secretion

• CFTR decreases ENaC activity → Low Na+ reabsorption

• Wet mucus

Airway epithelium with CF

• CFTR is inhibiting Cl- secretion

• Hyperactive ENaC → High Na+ reabsorption, water follows in

• Thick, viscous / dehydrated mucus

Sweat glands normally

• CFTR leads to Cl- reabsorption

• ENaC for Na+ reabsorption

Sweat glands with CF

• CFTR is inhibiting Cl- reabsorption

• Lower ENaC → Low Na+ reabsorption

• Salty sweat

Cl-, HCO3-

Pancreatic Duct CFTR channel interaction with SLC26

• CFTR leads to __ secretion in lumen, some __ secretion into lumen

SLC26

Anion exchanger that reabsorbs Cl- and secretes HCO3-

Cl-, SLC26, pH

Pancreatic duct CFTR dysfunction

• Decreased CFTR function → Decreased luminal __

• Thus decreased__ activity and exchange of ions

• Inappropriate luminal __

Class I Mutation

No functional CFTR protein, from nonsense mutation and severe outcomes

Class II Mutation

CFTR trafficking defect, from missense/misfolding and protein degraded

Class III Mutation

Defective CFTR channel regulation, from missense mutation at ATP-ADP exchange, can’t open

Class IV Mutation

Decreased CFTR channel conductance, from missense mutation, can’t bring Cl- out

Class V Mutation

Reduced synthesis of CFTR, from missense mutation and splicing issue

Class VI Mutation

Decreased CFTR stability, from missense mutation and reduced ½ life, degraded faster

Immunoreactive trypsinogen (IRT)

Newborn blood test, tracing pancreas content

Positive sweat test

Mild electric current pushes into skin to induce sweating, collected for salt content

60

CF sweat test results of __ or greater mmol/L indicative of CF diagnosis

bacterial, exocrine, azoospermia

CF Sx

• Airways - Severe chronic __ infection

• Pancreas - __ insufficiency

• Vas deferens - Obstructive __ (decrease sperm)

MLB2, IFRD1, SLC6A14

Genetic Effects on CF - (3) genes

MLB2 and SLC6A14 polymorphisms

Genetic modification → younger age for first p. aeruginosa infection

IFRD1 polymorphisms

Delays bacterial clearance from airway with less functional neutrophils

pseudomonas aeruginosa

Gram negative aerobic non-spore forming rod, antibiotic resistant

Biofilms, anaerobic

Dangers of pseudomonas aeruginosa are formations of __ upon attachment to lung epithelial membranes, in an __ environment

PTC Suppressors

For class I mutations and halt premature termination codons

Correctors

For class II mutations and protein folding defects

Potentiators

For class III mutations and gating effects

Triple combination therapy

1 potentiator with 2 correctors

Combination Therapy

For Class IV mutations, using potentiator and corrector

Amplifiers

For Class V mutations and reduced channel synthesis, increase mRNA

Stabilizers

For Class VI mutations and reduced stability in plasma membrane