Questions and Answers
What is the primary function of the CFTR protein?
What is the normal range of Cl- concentration in sweat?
What is the name of the gene that codes for the CFTR protein?
What is the purpose of the sweat test in diagnosing cystic fibrosis?
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What is the name of the protein family that CFTR belongs to?
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What is required to activate the CFTR channel?
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What percentage of cystic fibrosis alleles carry the F508del variant?
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What is the frequency of cystic fibrosis carriers in the general population?
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Which of the following is a characteristic of classical cystic fibrosis?
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What is the effect of the 5T variant on CFTR function?
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What is the relationship between CFTR genotype and pulmonary disease?
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What is the effect of mutant CFTR alleles on cholera toxin stimulation?
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What is the characteristic of congenital bilateral absence of the vas deferens (CBAVD)?
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What is the proportion of cystic fibrosis patients carrying at least one F508del allele?
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What is the relationship between sweat chloride levels and CFTR function?
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What is the role of modifier genes in cystic fibrosis?
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What is the function of Ivacaftor in the context of cystic fibrosis?
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What is the purpose of amiloride in the Ussing chamber experiment?
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Which of the following is used to activate CFTR in the Ussing chamber experiment?
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What type of epithelial cells are used in the Ussing chamber experiment?
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In which type of CFTR mutation is Ivacaftor more effective?
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In which journal was the study by Van Goor et al. published?
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What is the name of the medication approved by the EMA in 2020 and marketed in Europe as?
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What is the predicted median survival for patients with CF initiating Trikafta treatment between the ages of 12 and 17 years?
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In what year was the Breakthrough Prize awarded to Sabine Hadida, Paul Negulescu, and Fredrick Van Goor for the development of Trikafta?
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Which of the following sources provides information on Cystic Fibrosis and Congenital Absence of the Vas Deferens?
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In what year was the article 'Cystic fibrosis' by Ratjen et al. published?
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Which of the following articles discusses the application of CFTR modulators in cystic fibrosis?
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What is the outcome of treatment with lumacaftor in CF cell models?
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What is the method used to evaluate protein maturation in CF cell models?
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What is the effect of lumacaftor on non-CFTR misfolded proteins?
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What is the outcome of combined treatment with lumacaftor and ivacaftor in CF patients?
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What is the type of assay used to measure transepithelial chloride transport in CF cell models?
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What is the characteristic of lumacaftor compared to other CFTR correctors?
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What is the duration of treatment with lumacaftor-ivacaftor in the clinical trial?
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What is the effect of lumacaftor on CFTR protein in CF cell models?
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Study Notes
Cystic Fibrosis Diagnosis
- Sweat test is used for clinical diagnosis of CF
- Measures Cl- and Na+ in sweat following stimulation with pilocarpine
- CF: [Cl-] > 60 mM
- DNA test is used to confirm diagnosis
- CFTR gene: located on 7q31.2, codes for CFTR protein
- Anion channel for Cl- and HCO3-
- Expressed on apical surface of epithelial cells in exocrine organs
CFTR Protein Structure
- Member of ABC transporter family
- Consists of:
- 2 membrane spanning domains (MSD1 and MSD2)
- 2 intracellular nucleotide-binding domains (NBD 1 and NBD2)
- 1 intracellular regulatory domain (R domain)
- Consists of:
CFTR Variants
- >2000 variants, of which ~380 are CF-causing
- Most frequent variant: F508del (ΔF508)
- Deletion of Phe at aa 508
- Accounts for 50-70% of all CF alleles
- >80% of CF patients carry at least one copy
Global Distribution of CF
- Prevalence: 1 in 2500 live births
- Carrier frequency: 1/25
- Heterozygote advantage: protection against infectious diseases (e.g. cholera and typhoid fever)
Classification of Pathogenic CFTR Variants
- Classified into severe (minimal or no CFTR function) and mild (residual CFTR function)
- Correlation between CFTR function and clinical phenotype:
- Pancreatic insufficiency: good correlation
- Pulmonary disease: poor correlation
Genotype-Phenotype Correlation
- Pancreatic function: presence of 1 or 2 mild alleles → pancreatic sufficiency
- Pulmonary disease: variability in severity and age of onset among individuals with same CFTR genotype
Genetic Factors Contributing to Phenotypic Variability
- Combination of CFTR variants in trans or cis
- Poly(T) tract variants in intron 8
- Affects splicing of exon 9
- 5T variant → loss of exon 9 → reduced quality of functional CFTR
CFTR-Related Disorders
- Congenital bilateral absence of the vas deferens (CBAVD)
- Recurrent idiopathic pancreatitis
- Bronchiectasis
Correlation of CFTR Function with Sweat Chloride Levels and Clinical Phenotype
- Sweat chloride levels: correlation with CFTR function and clinical phenotype
- bronchiectasis: rare presentation in carriers, unclear correlation with CFTR genotype
CF Modifier Genes
- Variants in modifier genes contribute to variable severity of clinical manifestations in patients with same CFTR genotype
CFTR Modulators
- Ivacaftor (VX-770): acts as a CFTR potentiator to increase Cl- transport
- Lumacaftor (VX-809): corrects F508del CFTR trafficking and function
- Trikafta: combination of lumacaftor and ivacaftor
- Improves lung function in CF patients bearing homozygous F508del CFTR
- Approved by EMA and AIFA for prescription under the Italian public health service
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Description
This quiz assesses understanding of the sweat test used in diagnosing cystic fibrosis, including the measurement of chloride and sodium levels in sweat. It also covers the role of pilocarpine stimulation and the diagnostic criteria for CF.