Podcast
Questions and Answers
What are the 6 classes of CF mutations?
What are the 6 classes of CF mutations?
- Class 3: Defective ATP binding (correct)
- Class 5: Normal protein but less produced (correct)
- Class 6: Protein degraded more rapidly (correct)
- Class 2: Protein does not progress beyond the ER (correct)
- Class 1: No protein is produced (correct)
- Class 4: Defective ion conductance (correct)
Where is the gene associated with CF mapped to?
Where is the gene associated with CF mapped to?
Chr 7q31.2
How big is the CFTR gene?
How big is the CFTR gene?
90kb DNA, 27 exons
How big is the CFTR protein?
How big is the CFTR protein?
What is the CFTR protein?
What is the CFTR protein?
What are the 5 domains of the CFTR protein?
What are the 5 domains of the CFTR protein?
What does the carboxy terminal of CFTR protein do?
What does the carboxy terminal of CFTR protein do?
What is normal CFTR function in the airways compared to those with cystic fibrosis?
What is normal CFTR function in the airways compared to those with cystic fibrosis?
What is normal CFTR function in the lumen of the sweat duct compared to those with CF?
What is normal CFTR function in the lumen of the sweat duct compared to those with CF?
What are the most common CFTR mutations?
What are the most common CFTR mutations?
What happens in the F508del mutation?
What happens in the F508del mutation?
What are mutation class-specific therapies?
What are mutation class-specific therapies?
Why is acrylamide gel used in electrophoresis to test for F508del?
Why is acrylamide gel used in electrophoresis to test for F508del?
How does SNP analysis work?
How does SNP analysis work?
How does MALDI-TOF MS work?
How does MALDI-TOF MS work?
What is the inheritance of CF?
What is the inheritance of CF?
What are genotype-phenotype correlations in CF?
What are genotype-phenotype correlations in CF?
Study Notes
CF Mutations
- Six classes of cystic fibrosis (CF) mutations exist, each impacting the CFTR protein differently:
- Class 1: Nonsense and splice mutations lead to no protein production.
- Class 2: Protein is made but fails to progress beyond the endoplasmic reticulum (ER).
- Class 3: Protein reaches the plasma membrane but with defective regulation, preventing ATP hydrolysis.
- Class 4: Protein is partially open at the membrane, resulting in reduced ion conductance.
- Class 5: Normal protein produced in reduced quantities, often due to mutations in the promoter region.
- Class 6: Protein degrades rapidly.
Genetic Mapping
- The CF gene is located on chromosome 7q31.2.
CFTR Gene and Protein Characteristics
- CFTR gene spans 90kb of DNA and consists of 27 exons.
- The CFTR protein weighs 170 kDa and consists of 1480 amino acids.
- CFTR is a chloride channel protein, part of the ABC superfamily, regulated by ATP without active transport principles.
CFTR Protein Structure
- Comprised of:
- Two membrane-spanning domains for channel formation.
- Two nucleotide binding domains for ATP binding and hydrolysis.
- One regulatory domain with multiple cAMP-dependent phosphorylation sites.
Function and Role of CFTR
- The carboxy terminal anchors the CFTR protein to the cytoskeleton, influencing channel function and signal transduction at the apical plasma membrane.
- In the airways, normal CFTR function allows chloride and sodium regulation, maintaining mucus hydration. In cystic fibrosis, chloride exit is impaired causing dehydration of mucus.
- In sweat ducts, normal function allows reabsorption of chloride, sodium, and water. In CF, excess NaCl is present in sweat due to an absence of these ions in the lumen.
Common CFTR Mutations
- Frequent mutations include missense, frameshift, nonsense, and splicing variations, predominantly occurring in exons related to the membrane spanning and regulatory domains.
- The F508del mutation deletes phenylalanine, causing misfolding and ER retention, leading to degradation.
Therapeutic Approaches
- Specific treatments align with mutation classes:
- Class 1: Compounds to promote read-through.
- Class 2: "Correctors" enhance protein processing.
- Class 3: "Potentiators" activate the protein.
- Class 4: Flavonoid compounds improve channel function.
- Class 5: Aim to increase levels of properly spliced RNA.
Diagnostic Methods
- Acrylamide gel is employed in electrophoresis for distinguishing small mutation differences such as F508del.
- SNP analysis utilizes multiplex PCR to detect single nucleotide polymorphisms, indicated by fluorescently tagged peak colors from specific primers.
- MALDI-TOF mass spectrometry is leveraged for SNP genotyping by measuring the mass of PCR products.
Inheritance Patterns
- CF is inherited in an autosomal recessive manner, with higher incidence among Caucasians (1 in 2500-3000 births) and a carrier rate of 1 in 25.
- Prevalence varies globally, with Japanese populations showing 1 in 350,000 prevalence, also highlighting ethnic-specific mutations.
Genotype-Phenotype Correlations
- Classes 1, 2, 3, and potentially 6 mutations correlate with severe lung disease and pancreatic insufficiency.
- Classes 4 and 5 mutations are generally linked with pancreatic sufficiency and milder clinical presentations.
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Description
Test your knowledge on the 6 classes of mutations related to Cystic Fibrosis. This quiz covers various types of mutations including their effects on protein functionality and processing. Dive deep into the genetic factors of this condition.
