Genetics of Cystic Fibrosis

A set of flashcards for reviewing key concepts related to the genetics of cystic fibrosis, covering diagnosis, mutations, therapies, and clinical implications.

What is cystic fibrosis associated with in terms of genetics?

Cystic fibrosis is caused by mutations in the CFTR gene, leading to a defective chloride channel.

What type of inheritance pattern does cystic fibrosis follow?

Cystic fibrosis is a lethal autosomal recessive disorder.

What is the significance of the sweat test in diagnosing cystic fibrosis?

A sweat chloride level of ≥ 60 mmol/L indicates that CF is likely.

What does a sweat chloride level of 0 - 29 mmol/L indicate?

CF is unlikely regardless of age.

What characterizes cystic fibrosis as a pleiotropic disease?

It affects multiple organ systems with varied phenotypes.

What is the primary gene involved in cystic fibrosis?

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene.

What is the most common mutation associated with cystic fibrosis?

p.Phe508del (ΔF508) mutation.

How is the CFTR gene structured?

It has 27 exons and spans approximately 190 kb of genomic DNA.

What are the major classes of CFTR mutations?

Classes I-IV based on their effects on protein production and function.

What is a Class I mutation in CFTR?

Mutations that lead to no or reduced protein synthesis.

What type of mutation does Class II in CFTR represent?

Block in protein processing, such as the p.Phe508del mutation.

How do Class III mutations affect CFTR function?

They result in defective gating of the CFTR channel.

What mutation is an example of Class IV in CFTR?

p.Arg117His, which shows altered conductance of the channel.

Why is genotype/phenotype correlation important in cystic fibrosis?

It helps predict disease severity and informs treatment options.

What are the therapeutic approaches for cystic fibrosis listed in the lecture?

Gene therapy, small molecules for correction and potentiation, and protein supplementation.

Which test is mentioned to confirm the presence of cystic fibrosis mutations?

Molecular testing for known CFTR mutations.

What characterizes the CFTR protein structure?

It includes two transmembrane domains, two nucleotide binding domains, and one regulatory domain.

What does 'compound heterozygous' mean in the context of cystic fibrosis?

Having two different mutated alleles of the CFTR gene.

What is the significance of newborn screening for cystic fibrosis?

It helps to identify affected infants early for prompt intervention.

Which mutations are detected in standard multiplex tests for cystic fibrosis?

Common mutations like ΔF508, G542X, G551D, and others.

What recent improvement has been made regarding the life expectancy of cystic fibrosis patients?

Recent therapies have improved longevity significantly.

What are some key clinical features of cystic fibrosis?

Abnormal mucus production, digestive issues, and frequent lung infections.

What does elevated chloride indicate when found in sweat?

It is a hallmark sign of cystic fibrosis.

What is the role of CFTR modulators in cystic fibrosis therapy?

They aim to restore CFTR protein function.

What is the purpose of gene therapy in cystic fibrosis treatment?

It involves delivering a correct version of the CFTR gene to target cells.

How do small molecular drugs work in cystic fibrosis management?

They correct CFTR function or help the protein reach the cell membrane.

What is the potential downside of protein therapy for cystic fibrosis?

Delivery to cells can be ineffective and difficult to achieve.

What is ivacaftor used for in cystic fibrosis treatment?

It acts as a potentiator to enhance CFTR channel function.

Why was the drug Ataluren discontinued?

It did not meet its primary and secondary endpoints in trials.

What cultural demographic has a higher carrier frequency for cystic fibrosis?

Ashkenazi Jews, with a carrier frequency of 1 in 29.

What is the importance of the CFTR2 database?

It provides extensive information on CFTR variants.

What type of mutations does c.1521_1523delCTT represent?

It represents the ΔF508 or p.Phe508del mutation.

What is the relationship between CFTR mutations and disease severity?

Different mutations and their effects can lead to a spectrum of disease severity from mild to severe.

In cystic fibrosis, what does the term 'mucus alteration' refer to?

Therapies aimed at modifying the properties of mucus to improve clearance.

What is TOBI in the context of cystic fibrosis treatment?

Tobramycin, an anti-infective drug used in CF management.

What does the term 'sweat gland involvement' indicate in cystic fibrosis?

It indicates elevated chloride and sodium levels in sweat.

What clinical consequence is associated with Class IV mutations in cystic fibrosis?

Reduced open channel probability despite normal regulation.

What does 'phosphorylation of the regulatory domain' affect in CFTR?

It controls ATPase activity and Cl− channel opening.

Which variant is termed a 'read-through modulator' in therapy?

Ataluren, aimed at enhancing protein synthesis above premature stop codons.

How does hypertonic saline function as a therapy for cystic fibrosis?

It helps to restore airway surface liquid and mucus clearance.

What is the main challenge with CFTR gene therapy?

Getting the DNA into the cell nucleus.

What type of therapy does VX-522 represent?

It is an inhaled mRNA therapy aimed to deliver CFTR to lung cells.

How does ELX-02 work as a therapeutic agent?

It promotes read-through of premature stop codons in CFTR.

What does combination therapy in cystic fibrosis treatment involve?

Using multiple drugs that target different aspects of CFTR dysfunction.

What are the implications of the findings related to CFTR mutation distribution?

Mutations are population-specific, with some variations contributing to most cases.