A Dive Into Cystic Fibrosis

A Dive Into Cystic Fibrosis

Interactive Learning Module

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Pathology 3500: Pulse Assignment, Winter 2026Department of Pathology and Laboratory Medicine, Western University. Group #13

Table of Contents

Click each button to jump to a section! To get started, select "Introduction".

Mode of Inheritance

Pathogenesis

Introduction

Etiology

Signs and Symptoms

Diagnostic Criteria

Treatment Options

Complications

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Canadian Cystic Fibrosis Research

Prognosis

Case Studies

Introduction

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Case Study #1

Try to find the diagnosis!

After completing this module, you will be able to revisit this case study.

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Introduction

What is cystic fibrosis?

• Cystic fibrosis (CF): the most common, fatal, genetic disease affecting Canadians children and young adults.

• Caused by mutations in the gene that produces the cystic fibrosis transmembrane conductance regulator protein (CFTR) (3).

• “Causes abnormally thick mucus secretions that disrupt normal molecular transport, exchange, and exocrine gland functions” (4).

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Introduction

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Function

• CFTR: an important epithelial ion (i.e. chloride and bicarbonate) channel protein (4).

• Ion channel helps atoms or molecules with an electrical charge cross the cell membrane (5).

• Ion transport is an integral part of keeping internal body homeostasis, proper action potentials, and proper signalling.

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Introduction

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Function

• CFTR in the lungs moves chloride ions from inside to outside the cell.

• After negative chloride ions move outside, they bring positive sodium ions (which brings water outside).

• Moving water out is vital to ensure mucus remains moist so that cilia in the lungs can sweep back and forth to clear debris (5).

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Mode of Inheritance

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Mode of Inheritance

Molecular Genetic Basics

• CFTR gene: located on chromosome 7.

• CF is a autosomal recessive condition (both alleles must be mutated in order to result in CF).

• Two carrier parents have a 25% chance of having an affected child (50% carriers, 25% unaffected totally) (3).

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Mode of Inheritance

• Allelic heterogeneity: many disease-causing mutations in CFTR identified (6).
• Different mutations in the CFTR genes can all cause cystic fibrosis, but all are located within that gene.

• Variable expressivity and genotype- phenotype correlation is observed (6).

• One mutation in the CFTR gene may not cause the same disease state as another.
• Each class of disease is defined by different mutations, with ranging severity.

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Mode of Inheritance

• The resulting phenotype will depend on the inherited mutation(s).

• Depending on the mutation(s) of the parent (if any), the recessive alleles of disease-affected children can be homozgyous or heterozygous.

Click on each below to learn more.

Homozygous inheritance

Heterozygous inheritance

Homozygous inheritance

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Molecular Genetic Basis

Allele Homozygosity

One F508del Mutation

One F508del Mutation

• Both parents have the same mutation (F508del).

• The autosomal recessive pattern generates the following results in children:
• 25% unaffected state; no mutations inherited.
• 50% carrier state; one F508del mutation inherited.
• 25% diseased state; two F508del mutations inherited (5).

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RETURN TO OPTIONS

No F508del Mutation

One F508del Mutation

One F508del Mutation

Two F508del Mutations

Molecular Genetic Basis

Allele Heterozygosity

• Both parents have different mutations.

• The autosomal recessive pattern generates the following results in children:
• 25% unaffected state; no mutations inherited.
• 25% carrier state; one F508del mutation inherited.
• 25% carrier state; one G551D mutation inherited.
• 25% diseased state; two different mutations inherited.
• Combined phenotype of F508del and G551D cystic fibrosis state.

• All carrier children are equally likely to get one mutation over the other (5).

One G551D Mutation

One F508del Mutation

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Two Different Mutations (F508del and G551D)

Practise Question

One F508del Mutation

One G551D Mutation

No F508del Mutation

Test Your Knowledge #1

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Etiology

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Etiology: Mutation Variety

Click on the button below each image to reveal mutations that cause cystic fibrosis.

CLASS I

NORMAL

CLASS II

CLASS V

CLASS IV

CLASS II

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Clicking through each will allow you to advance to the next section.

NORMAL

• CFTR protein is transcribed and translated appropriately.

• CFTR is transported, processed and folded corrected, and inserted into the cell membrane.

• Proper transport of chloride (Cl-) ions into a cell, causing sodium (Na+) efflux via ENaC channels (3).

• Balance of ion transport for function.

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(8)

Click to return to mutations list

CLASS I MUTATIONS

Protein Production Mutations

• CFTR is made of 1,480 amino acids and must be assembled appropriately.

• Class I mutations: include nonsense (improper stop codon) or splicing defects (5).
• Resulting CFTR proteins are typically non-functional.

• Examples: G542X, W1282X, R553X (8).

(8)

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Click to return to mutations list

CLASS II MUTATIONS

Protein Processing Mutations

• CFTR is made of 1,480 amino acids and must be folded properly.

• Class II mutations: involve the protein's 3D conformation, internal bonds and external interacting residues.
• Resulting CFTR proteins are typically targetted for degredation within the cells and never make it to the membrane (3, 5, 8).

• Examples: F508del (most common!), N1203K, I507del (8).

(8)

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Click to return to mutations list

CLASS III MUTATIONS

Gating Mutations

• CFTR must be able to sufficiently transport ions across the membrane.

• Class III mutations: can block the 'gates' by which Cl- passes through, or never activate it to open.

• Resulting CFTR proteins are typically transported, produced and folded appropriately but cannot function.

• Examples: G551D, S549N, V520F (8).

(8)

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Click to return to mutations list

CLASS IV MUTATIONS

Conduction Mutations

• CFTR must be able to sufficiently transport ions across the membrane.

• Class IV mutations: interfere with Cl- ability to move through the 'gate' as well, and can make transport much slower or difficult.

• Resulting CFTR proteins have a mechanism to move ions, but struggle facilitating that movement (3, 5).

• Examples: R117H, D1152H, R347P (8).

(8)

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Click to return to mutations list

CLASS V MUTATIONS

Quantity Mutations

• Class V mutations: result in insufficient amounts of CFTR at the membrane surface.
• Results in a defect in any protein production and transport mechanisms (transcription, translation, processing, folding, etc.).
• Resulting CFTR proteins work properly, but ion movement is slow compared to Wild-type (3, 5).

• Examples: 3849+10kbC->T, 2789+5G->A, A455E (8).

(8)

Practise Question

Test Your Knowledge #2

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Pathogenesis

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Pathogenesis

• Primary defect in CF: reduced production or abnormal function of CFTR.

• Caused by mutations and/or defects in transporting CFTR to the cell surface or membranes, or in the CFTR function itself.
• Disruptive mutations in CFTR render epithelial membranes relatively impermeable to chloride ions.
• Mutations in CFTR genes may cause epithelial membranes to be impermeable to chloride ions (4).

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Pathogenesis

• Respiratory: abnormally thick mucus can cause airway obstruction.

• Patients with CF have decreased chloride secretion and increased sodium and water reabsorption in the airways.
• Leads to dehydration of the mucus layer coating epithelial cells, defective mucociliary action, and mucous plugging (4).

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Pathogenesis

• Major function of CFTR in the sweat gland ducts is to reabsorb luminal chloride ions, as well as sodium reabsorption through the epithelial sodium channel (ENaC).
• CF: loss of CFTR function in the sweat duct causes increased chloride and sodium concentration in sweat.

• GI and pancreas: pancreatic duct, cystic duct, and intestinal lumen secretions become thick, obstructing each of their lumens (4).

(10)

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Test Your Knowledge #3

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Signs and Symptoms

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Signs and Symptoms

Respiratory System

Digestive System

Other Systems

• Greasy stools with a bad smell (steatorrhea).
• Intestinal obstruction.
• Difficulty gaining weight.
• Rectal prolapse.
• Meconium ileus (difficulty passing first stool in newborns, causing intestinal obstruction) (11).

• Chronic, productive cough.
• Wheezing.
• Recurring lung or sinus infections.
• Stuffy nose and irritated nasal passages (11).

• Excessive salt (NaCl) in sweat.
• Fertility issues (about 98% of men are infertile and women with CF experience more fertility issues than women without CF) (11).

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Practise Question

Test Your Knowledge #4

Practise Question

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Test Your Knowledge #4

Practise Question

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Complications

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Complications

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Liver

Respiratory

GI and Pancreatic

• Pathogens can colonize and multiply, causing further complications.

• Recurrent lung infections result in persistent inflammatory responses, which can lead to chronic lung issues.

• Pancreatic duct obstructions: malabsorption, maldigestion.

• Cystic duct obstructions: bile is unable to reach duodenum.

• Bile duct obstruction; hepatic steatosis, biliary cirrhosis (secondary liver damage).

Practise Question

Test Your Knowledge #6

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Diagnostic Criteria

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Diagnostic Criteria

• To diagnose CF, both of the following criteria must be met:
• One of the following: clinical symptoms consistent with CF in at least one organ system, positive newborn screen, or having a sibling with CF.

• And: evidence of CFTR dysfunction (any of the following):
• Elevated sweat chloride (≥60 mmol/L).
• Presence of two disease-causing mutations in the CFTR gene, one from each parental allele.
• Abnormal nasal potential difference (NPD).
• Measures electrical potential across the nasal epithelium to check ENaC and CFTR function (16).

Sweat chloride test (15)

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Treatment Options

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Treatment Options

• CFTR modulators.
• Vitamins.
• Enzymes: helps the body digest fats, proteins, and carbohydrates.

• Treat respiratory complications:
• Antibiotics: treat bacterial infections.
• Inhaled medications: increase size of air passages in the lungs.

• Mucolytics: break up or thin mucus to prevent airway blockage.
• Corticosteroids: reduce lung inflammation and mucus plugging (18).

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CFTR Modulators

• Small-molecule medications.

• Two types:
• Correctors: improve folding and trafficking of mutant CFTR from the endoplasmic reticulum to the cell surface.
• Potentiators: increase gating function of CFTR by raising the channel-open probability (PO) to keep them open for longer (19).

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CFTR Modulators

• CFTR modulators depend on which mutation a CF patient has and includes (20-21):

• Kalydeco (ivacaftor).
• Alyftrek (vanzacaftor/tezacaftor/deutivacaftor): not available in Canada.
• Trikafta (elexacaftor/tezacaftor/ivacaftor).
• Symdeko (tezacaftor/ivacaftor).
• Orkambi (lumacaftor/ivacaftor).

• This module will touch upon one common modulator in detail: Kalydeco.

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Kalydeco

Kalydeco (Ivacaftor)

• First-generation modulator.

• Works by potentiating the CFTR protein.

• Increases the channel-opening probability (gating) of the CFTR protein.

• Authorized for use by CF patients who are two months of age or older and have one of the following mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H (23).

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Nutrition - Enzymes and Vitamins

• CF patients struggle to absorb nutrients, particularly fat.

• Enzymes help the body digest fats, proteins and complex carbohydrates.
• CF patients require increased fat-soluble vitamins (Vitamins A, D, E, and K) due to decreased absorption.
• Deficits can cause bleeding, back discomfort, bone fractures, and night blindness (24).

• Green leafy vegetable

• Liver
• Vegetable oils.
• Also produced by intestinal flora

• Liver
• Dairy products
• Egg yolk
• Yellow or green leafy vegetables

• Fish
• Egg yolk
• Fortified milk and margarine
• Liver

• Nuts
• Eggs
• Wheat germ
• Vegetable oils

Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

Vitamin K-Rich Food

Vitamin D-Rich Food

Title

Vitamin A-Rich Food

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Vitamin E-Rich Food

Title

Title

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Test Your Knowledge #7

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Canadian Cystic Fibrosis Research

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Canadian Cystic Fibrosis Research

"Exploring the Fetal Origins of Cystic Fibrosis Lung Disease"

“Development of Synthetic Chloride Channels and Transporters”

"Quantifying the Neurocognitive Impacts of CFTR Modulators"

• University of British Columbia: Jonathan Rayment is researching the side effects of CFTR modulators and how to relieve them.
• Patients have reported brain fog, anxiety and other mental/neuronal symptoms (25).

• Queen's University: Dr.Lee is investigating the creation of artificial compounds that might aid in the restoration of chloride ion (salt) movement in cells (25).

• University of Toronto: Amy Wong is researching how CF affects lung tissue by using lab-grown models to identify key genes and biological processes.
• Aims to determine when lung development starts to deviate from normal.
• Can lead to earlier (even prenatal) diagnosis and possibly of preventative CF medications (25).

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Prognosis

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Prognosis

• Predicted life expectancy for someone born with CF over the past few years: around 50 years old.
• Has greatly increased the median age of CF patients since in the 1980s due to treatment improvements.
• Used to be a childhood illness; has now evolved to an adult chronic condition (27).

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Prognosis

• Prognosis depends on the severity of disease.

• There is no cure for cystic fibrosis.

• Treatment works best with early diagnosis (highlights importance of newborn screening).
• Prenatal genetic testing can help determine whether an individual is a CFTR gene variant carrier (27).

(26)

Practise Question

Test Your Knowledge #8

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Case Studies

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Case Study #1 (Revisited)

Try to find the diagnosis!

Title

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Flip for answer

Cystic fibrosis

Subtitle

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Case Study #2 (Revisited)

Try to find the diagnosis!

Title

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Cystic fibrosis

Subtitle

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