leky-latky/cftr-protein/mutace/F508del

Deletion of phenylalanine at position 508 in the polypeptide chain (F508del)

• Present in 85% of CF patients in at least one allele
• Majority of mutant CFTR protein to be retained in the endoplasmic reticulum (ER)
• With premature degradation by the ubiquitin-proteasome system (Riordan, 2008).
• F508del-CFTR
• Can also accumulate at the PM when the trafficking defect is rescued by
• Chemical, genetic, or physical strategies
• Small molecule compounds,
• Second-site mutations
• Low temperature (Amaral and Farinha, 2013)
• Rescued F508del-CFTR exhibits
• Defective channel gating
• Can be partially due to defective phosphorylation (Pasyk et al., 2015)
• Decreased stability
• Biochemical half-life at the PM is about 4 h compared to that of wt-CFTR that exceeds 48 h (Heda et al., 2001)
• Due to more rapid endocytosis of mutant CFTR protein and/or its selective targeting for lysosomal degradation (Swiatecka-Urban et al., 2005)
• F508del-CFTR recycling
• Attenuated by nearly five-fold as compared with wt-CFTR
• Misfolding of CFTR has also a major impact on the sequestration of CFTR at the early endosome (Sharma et al., 2004).

• www.frontiersin.org/articles/10.3389/fchem.2016.00001/full

• Mutation will produce an abnormal CFTR protein
• Lacks this phenylalanine residue and which cannot fold properly
• Does not escape the endoplasmic reticulum for further processing.
• Having two copies of this mutation (one inherited from each parent) is by far the most common cause of cystic fibrosis (CF), responsible for nearly two-thirds of cases worldwide

• en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

• In cca 90% of patients
• Impairs both channel surface expression (Cheng et al., 1990) and open probability (Miki et al., 2010).

• elifesciences.org/articles/46450

Nosičství CFTR Phe508del (rs113993960)

• Genotyped 108 035 randomly selected white Danish individuals aged 20–100 from the Copenhagen General Population Study
• Assessed risks during up to 15 years follow-up (median:9 years)
• A single individual was excluded due to homozygosity for CFTR Phe508del and known cystic fibrosis
• Among 108 034 individuals
• 105 176(97%) were non-carriers
• 2858(3%) were carriers - heterozygous for CFTR Phe508del
• Survival was similar between carriers and non-carriers
• Multivariable adjusted, carriers had
• Odds ratio of 1.31(95% confidence interval:1.16–1.48) for chronic bronchitis
• Hazard ratio of 1.88(1.03–3.45) for bronchiectasis
• Hazard ratio of 1.52(1.12–2.08) for lung cancer
• Carriers did not differ from non-carriers concerning lung function or any other morbidity
• Carriers of CFTR Phe508del have a normal lifespan
• But an increased risk of chronic bronchitis by 1.3-fold, bronchiectasis by 1.9-fold, and lung cancer by 1.5-fold.

• erj.ersjournals.com/content/early/2020/05/07/13993003.00558-2020

Heterozygous carrier

• Decreased water loss during diarrhea
• Because malfunctioning or absent CFTR proteins cannot maintain stable ion gradients across cell membranes
• Build-up of both Cl- and Na+ ions inside affected cells
• Creating a hypotonic solution outside the cells
• Causing water to diffuse into the cells by osmosis
• Several studies indicate that heterozygous carriers are at increased risk for various symptoms
• Increased airway reactivity
• Poor pulmonary function
• Wheeze have been shown to be at higher risk for poor pulmonary function or development and progression of chronic obstructive lung disease
• One gene for cystic fibrosis is sufficient to produce mild lung abnormalities even in the absence of infection

• en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

• ?F508 is present on at least one copy of chromosome 7 in approximately one in 30 Caucasians
• ?F508 heterozygotes may be overrepresented among individuals with asthma
• May have poorer lung function than non-carriers
• Carriers of a single CF mutation have a higher prevalence of chronic rhinosinusitis than the general population

• en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

Homozygous ?F508 mutation

• Prevents the CFTR protein from assuming its normal position in the cell membrane
• Increased water retention in cells
• Corresponding dehydration of the extracellular space
• Associated cascade of effects on various parts of the body
• Thicker mucous membranes in the epithelia of afflicted organs
• Obstruction of narrow respiratory airways
• Inhibition of the free movement of mucocilia
• Congenital absence of the vas deferens
• Due to increased mucus thickness during fetal development
• Pancreatic insufficiency
• Due to blockage of the pancreatic duct with mucus
• Increased risk of respiratory infection
• Due to build-up of thick, nutrient-rich mucus where bacteria thrive

• en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

• Approximately 50% of cystic fibrosis cases in Europe are due to homozygous ?F508 mutations
• The allele frequency of ?F508 is about 70%
• Remaining cases are caused by over 1,500 other mutations, including
• R117H, 1717-1G>A, and 2789+56G>A
• Combined with each other or even a single copy of ?F508, may cause CF symptoms
• Genotype is not strongly correlated with severity of the CF

• en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

• Homozygous for F508del-CFTR
• Lumacaftor (VX809) improves mutant CFTR trafficking to the cell surface
• Combined with ivacaftor (VX770)
• Improves clinical outcomes including lung function
• Cca 3% increase in forced expiratory volume in 1 second [FEV1]
• Reduced risk of pulmonary exacerbation
• These results are modest relative to ivacaftor monotherapy in patients with gating-class CFTR mutations

• insight.jci.org/articles/view/93029