Materiały źródłowe

• #1 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #2 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #3 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #4 Cystic fibrosis transmembrane conductance regulator – Wikipedia

  https://en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

  Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with CF (cystic fibrosis). The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations of the CFTR gene affecting anion channel function lead to dysregulation of epithelial lining fluid (mucus) transport in the lung, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing vas deferens (spermatic cord) and epididymis appear to result from abnormal intraluminal secretions, causing congenital absence of the vas deferens and male infertility, and found associated with an imbalance of fatty acids.

• #5 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  The CFTR gene is located at 7q31.2. More than 1900 mutation have been identified of which F508del (deletion of three bases coding for phenylalanine at the 508th position) is the most common. […] Class II mutations contribute to protein processing abnormality leading to aberrant localization. […] Class III mutations contribute to protein regulation abnormalities leading to a decreased activity. […] Class IV mutations contribute to protein conduction abnormalities leading to altered frequency of ion flow. […] Class V mutations lead to a reduced amount of functional CFTR protein and class VI mutation cause an enhanced protein turnover. […] The current and future therapeutic targets are mainly focused on correcting structural and functional abnormalities of CFTR protein. […] A new group of drugs called CFTR modulators are available which are able to correct the basic defect in CF, i.e. CFTR protein itself though the exact mechanism is not fully elucidated.

• #6 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #7 CFTR – Johns Hopkins Cystic Fibrosis Center

  https://hopkinscf.org/knowledge/cftr/

  The location of the CFTR protein, which is found in several organs, determines where the symptoms of CF occur. The organs that are typically involved in CF are the skin, pancreas and lungs. […] More than 2500 different mutations in the CFTR gene have been described. Most of these mutations either substitute one base the building material of DNA for another, or delete a small number of DNA bases. The most common CFTR mutation, present in approximately 70 percent of people with CF, is F508del. This mutation is caused by the deletion of three base pairs of the CFTR gene leading to the loss of an amino acid called phenylalanine, abbreviated F, in the CFTR protein. […] Mutations in the CFTR gene can lead to different changes in the CFTR protein. These changes are grouped into 6 classes. People with CF who have some residual CFTR function (Classes 4, 5 6) tend to have milder or later onset of symptoms.

• #8 7.6: Cystic Fibrosis in Humans – Biology LibreTexts

  https://bio.libretexts.org/Bookshelves/Genetics/Introduction_to_Genetics_(Singh)/07%3A_The_Central_Dogma_-_Mutations_and_Biochemical_Pathways/7.06%3A_Cystic_Fibrosis_in_Humans

  Cystic fibrosis (CF) is one of many diseases that geneticists have shown to be primarily caused by mutation in a single, well-characterized gene. The disease is due to a mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which was first identified by Lap-chee Tsui’s group at the University of Toronto (Tsui, 1995). Epithelial tissues in some organs rely on the CFTR protein to transport ions (especially Cl-) across their cell membranes. If there is insufficient activity of CFTR, an imbalance in ion concentration results, which disrupts the properties of the liquid layer that normally forms on the epithelial surface. In the lungs, this causes mucus to accumulate and can lead to infection. Defects in CFTR also affect pancreas, liver, intestines, and sweat glands all of which need this ion transport. Over one thousand different mutant alleles of CFTR have been described. Any mutation that prevents CFTR from sufficiently transporting ions can lead to cystic fibrosis (CF). Worldwide, the most common CFTR allele among CF patients is called F508 (delta-F508; or PHE508DEL), which is a deletion of three nucleotides that eliminates a phenylalanine from position 508 of the 1480 aa wild-type protein. Mutation F508 causes CFTR to be folded improperly in the endoplasmic reticulum (ER), which then prevents CFTR from reaching the cell membrane. CFTR is also notable because it is one of the well-characterized genetic diseases for which a drug has been developed that compensates for the effects of a specific mutation. The drug, Kalydeco (Ivacaftor), was approved by the FDA and Health Canada in 2012, decades after the CFTR gene was first mapped to DNA markers (in 1985) and cloned (in 1989). Kalydeco compensates for this mutation by binding to CFTR and holding it in an open conformation. […] The G551D mutation affects the ability of ATP to bind to CFTR and open the channel it for transport.

• #9 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #10 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #11 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #12 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  The CFTR gene is located at 7q31.2. More than 1900 mutation have been identified of which F508del (deletion of three bases coding for phenylalanine at the 508th position) is the most common. […] Class II mutations contribute to protein processing abnormality leading to aberrant localization. […] Class III mutations contribute to protein regulation abnormalities leading to a decreased activity. […] Class IV mutations contribute to protein conduction abnormalities leading to altered frequency of ion flow. […] Class V mutations lead to a reduced amount of functional CFTR protein and class VI mutation cause an enhanced protein turnover. […] The current and future therapeutic targets are mainly focused on correcting structural and functional abnormalities of CFTR protein. […] A new group of drugs called CFTR modulators are available which are able to correct the basic defect in CF, i.e. CFTR protein itself though the exact mechanism is not fully elucidated.

• #13 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #14 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #15 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Cystic fibrosis is caused by over 2,000 possible mutations in the CFTR gene, each disrupting chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances. […] Modern understanding began in 1949 when scientists identified the autosomal recessive inheritance pattern of cystic fibrosis and linked the disease to a defect in the CFTR protein, a chloride channel crucial for regulating salt and water balance in the body. […] CFTR disease-causing mutations have been categorized into the following dysfunctional variants, classes I through V: Class I dysfunction results from nonsense, frameshift, or splice-site mutations that terminate the mRNA sequence prematurely. […] Class II dysfunction results in abnormal or dysfunctional posttranslational processing of CFTR that prohibits normal intracellular protein transit.

• #16 Cystic fibrosis gene mutations: evaluation and assessment of disease s | AGG

  https://www.dovepress.com/cystic-fibrosis-gene-mutations-evaluation-and-assessment-of-disease-se-peer-reviewed-fulltext-article-AGG

  A strategy to overcome premature termination codons (PTC) in class I mutations is to reduce ribosomal translational fidelity. […] Class II mutations, including Phe508del, create a CFTR conformational abnormality that prevents adequate folding. […] The protein is rapidly recognized by the endoplasmic reticulum quality control mechanism and degraded before it can reach its target site, the apical cellular surface. […] The molecules previously described target either the structure or the function of CFTR-mutant protein. […] Although CF mutation identification is a fundamental step in stratified medicine, this information is virtually insignificant if not correlated with the intrinsic molecular defect.

• #17 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Class III dysfunction is characterized by diminished protein activity in response to intracellular signaling. […] Class IV dysfunction results in a protein that correctly localizes to the cell surface. […] Class V dysfunction is the net decreased concentration of CFTR channels in the cellular membrane due to rapid degradation by cellular processes. […] All mutations result in decreased chloride secretion and, consequently, increased sodium resorption into the cellular space. […] The increased sodium reabsorption leads to increased water resorption and manifests as thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues. […] Thickened mucus secretions in nearly every affected organ system result in mucous plugging with obstruction pathologies.

• #18 7.6: Cystic Fibrosis in Humans – Biology LibreTexts

  https://bio.libretexts.org/Bookshelves/Genetics/Introduction_to_Genetics_(Singh)/07%3A_The_Central_Dogma_-_Mutations_and_Biochemical_Pathways/7.06%3A_Cystic_Fibrosis_in_Humans

  Cystic fibrosis (CF) is one of many diseases that geneticists have shown to be primarily caused by mutation in a single, well-characterized gene. The disease is due to a mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which was first identified by Lap-chee Tsui’s group at the University of Toronto (Tsui, 1995). Epithelial tissues in some organs rely on the CFTR protein to transport ions (especially Cl-) across their cell membranes. If there is insufficient activity of CFTR, an imbalance in ion concentration results, which disrupts the properties of the liquid layer that normally forms on the epithelial surface. In the lungs, this causes mucus to accumulate and can lead to infection. Defects in CFTR also affect pancreas, liver, intestines, and sweat glands all of which need this ion transport. Over one thousand different mutant alleles of CFTR have been described. Any mutation that prevents CFTR from sufficiently transporting ions can lead to cystic fibrosis (CF). Worldwide, the most common CFTR allele among CF patients is called F508 (delta-F508; or PHE508DEL), which is a deletion of three nucleotides that eliminates a phenylalanine from position 508 of the 1480 aa wild-type protein. Mutation F508 causes CFTR to be folded improperly in the endoplasmic reticulum (ER), which then prevents CFTR from reaching the cell membrane. CFTR is also notable because it is one of the well-characterized genetic diseases for which a drug has been developed that compensates for the effects of a specific mutation. The drug, Kalydeco (Ivacaftor), was approved by the FDA and Health Canada in 2012, decades after the CFTR gene was first mapped to DNA markers (in 1985) and cloned (in 1989). Kalydeco compensates for this mutation by binding to CFTR and holding it in an open conformation. […] The G551D mutation affects the ability of ATP to bind to CFTR and open the channel it for transport.

• #19 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Class III dysfunction is characterized by diminished protein activity in response to intracellular signaling. […] Class IV dysfunction results in a protein that correctly localizes to the cell surface. […] Class V dysfunction is the net decreased concentration of CFTR channels in the cellular membrane due to rapid degradation by cellular processes. […] All mutations result in decreased chloride secretion and, consequently, increased sodium resorption into the cellular space. […] The increased sodium reabsorption leads to increased water resorption and manifests as thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues. […] Thickened mucus secretions in nearly every affected organ system result in mucous plugging with obstruction pathologies.

• #20 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  The CFTR gene is located at 7q31.2. More than 1900 mutation have been identified of which F508del (deletion of three bases coding for phenylalanine at the 508th position) is the most common. […] Class II mutations contribute to protein processing abnormality leading to aberrant localization. […] Class III mutations contribute to protein regulation abnormalities leading to a decreased activity. […] Class IV mutations contribute to protein conduction abnormalities leading to altered frequency of ion flow. […] Class V mutations lead to a reduced amount of functional CFTR protein and class VI mutation cause an enhanced protein turnover. […] The current and future therapeutic targets are mainly focused on correcting structural and functional abnormalities of CFTR protein. […] A new group of drugs called CFTR modulators are available which are able to correct the basic defect in CF, i.e. CFTR protein itself though the exact mechanism is not fully elucidated.

• #21 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Class III dysfunction is characterized by diminished protein activity in response to intracellular signaling. […] Class IV dysfunction results in a protein that correctly localizes to the cell surface. […] Class V dysfunction is the net decreased concentration of CFTR channels in the cellular membrane due to rapid degradation by cellular processes. […] All mutations result in decreased chloride secretion and, consequently, increased sodium resorption into the cellular space. […] The increased sodium reabsorption leads to increased water resorption and manifests as thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues. […] Thickened mucus secretions in nearly every affected organ system result in mucous plugging with obstruction pathologies.

• #22 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #23 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #24 Cystic Fibrosis: Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9358-cystic-fibrosis

  CFTR usually makes a gate for chloride ions, a type of mineral with a negative electrical charge. Chloride moves out of the cell, taking water with it, which thins out mucus and makes it more slippery. In people with CF, gene mutations in CFTR prevent this from happening, so the mucus stays sticky and thick. […] There are different categories (classes I to VI) of gene mutation in CFTR that depend on the effect they have. Some produce no proteins at all, some produce only small amounts of proteins, and some produce proteins that don’t work properly. […] Yes, cystic fibrosis is a genetic condition that you’re born with. People who have CF inherit two mutated CFTR genes, one from each biological parent (it’s inherited in an autosomal recessive manner). […] Complications of CF include: Thick mucus can trap bacteria in your lungs and airways that you can’t clear out. This can lead to frequent infections. […] CFTR modulators are medications that can help correct issues with proteins made by mutated CFTR genes and increase the amount of functioning proteins on your cells’ surfaces. They’re not a cure for CF. But for certain people, they’ve made dramatic improvements in symptoms and life expectancy.

• #25 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  Class III dysfunction is characterized by diminished protein activity in response to intracellular signaling. […] Class IV dysfunction results in a protein that correctly localizes to the cell surface. […] Class V dysfunction is the net decreased concentration of CFTR channels in the cellular membrane due to rapid degradation by cellular processes. […] All mutations result in decreased chloride secretion and, consequently, increased sodium resorption into the cellular space. […] The increased sodium reabsorption leads to increased water resorption and manifests as thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues. […] Thickened mucus secretions in nearly every affected organ system result in mucous plugging with obstruction pathologies.

• #26 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #27 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. […] Six classes of defects resulting from CFTR mutations have been described: Complete absence of CFTR protein synthesis, Defective protein maturation and early degradation (caused by the most common mutation, F508), Disordered regulation (diminished ATP binding and hydrolysis), Defective chloride conductance or channel gating, Diminished transcription due to promoter or splicing abnormality, Accelerated channel turnover from the cell surface.

• #28

  https://link.springer.com/article/10.1023/A:1022402105375

  In recent years a new family of transport proteins called ABC transporters has emerged. One member of this novel family, called CFTR (cystic fibrosis transmembrane conductance regulator), has received special attention because of its association with the disease cystic fibrosis (CF). This is an inherited disorder affecting about 1 in 2000 Caucasians by impairing epithelial ion transport, particularly that of chloride. […] The purpose of this introductory review in this minireview series is to summarize what we and others have learned during the past eight years about the structure and function of the first nucleotide binding domain (NBF1 or NBD1) of the CFTR protein and the effect thereon of disease-causing mutations. The relationship of these new findings to the pathogenesis of CF is also discussed.

• #29 Basics of the CFTR Protein | Cystic Fibrosis Foundation

  https://www.cff.org/research-clinical-trials/basics-cftr-protein

  Cystic fibrosis occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is either not made correctly, or not made at all. […] The cystic fibrosis transmembrane conductance regulator (CFTR) protein helps to maintain the balance of salt and water on many surfaces in the body, such as the surface of the lung. When the protein is not working correctly, chloride a component of salt becomes trapped in cells. Without the proper movement of chloride, water cannot hydrate the cellular surface. This leads the mucus covering the cells to become thick and sticky, causing many of the symptoms associated with cystic fibrosis. […] To understand how mutations in the CFTR gene cause the protein to become dysfunctional, it is important to understand how the protein is normally made, and how it helps to move water and chloride to the cell surface.

• #30 Cystic fibrosis – Wikipedia

  https://en.wikipedia.org/wiki/Cystic_fibrosis

  The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. […] Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. […] The current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. […] The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body’s immune system, causing repeated respiratory infections.

• #31 CFTR – Johns Hopkins Cystic Fibrosis Center

  https://hopkinscf.org/knowledge/cftr/

  The cystic fibrosis transmembrane conductance regulator (CFTR) is defective in cystic fibrosis (CF). This protein is a channel that sits on the surface of cells and transports chloride and other molecules, such as bicarbonate. Mutations in this gene lead to CF. Since the discovery of the CFTR gene in 1989, more than 2,500 mutations have been identified. […] Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a chloride channel located on the surface of certain epithelial cells. […] The CFTR protein is composed of 1,480 amino acids and is located on the surface of many cells in the body. The CFTR protein contains a single chain of amino acids that are grouped in five functional regions called domains. Two transmembrane domains (TMD1 and TMD2), two cytoplasmic nucleotide-binding domains (NBD1 and NBD2) and a regulatory (R) domain make up the CFTR protein. Each domain has a special function when it comes to transporting chloride through the cell surface. Therefore, mutations in different domains cause a range of CF symptoms depending on the extent that chloride transport is affected. Mutations in CFTR often affect the three-dimensional structure of the protein and prevent CFTR from reaching the membrane.

• #32 Cystic fibrosis transmembrane conductance regulator – Wikipedia

  https://en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

  The CFTR gene is located on the long arm of chromosome 7, at position q31.2, and ultimately codes for a sequence of 1,480 amino acids. Normally, the three DNA base pairs A-T-C (paired with T-A-G on the opposite strand) at the gene’s 507th position form the template for the mRNA codon A-U-C for isoleucine, while the three DNA base pairs T-T-T (paired with A-A-A) at the adjacent 508th position form the template for the codon U-U-U for phenylalanine. The F508 mutation is a deletion of the C-G pair from position 507 along with the first two T-A pairs from position 508, leaving the DNA sequence A-T-T (paired with T-A-A) at position 507, which is transcribed into the mRNA codon A-U-U. Since A-U-U also codes for isoleucine, position 507’s amino acid does not change, and the mutation’s net effect is equivalent to a deletion of the sequence resulting in the codon for phenylalanine at position 508.

• #33 CFTR – Johns Hopkins Cystic Fibrosis Center

  https://hopkinscf.org/knowledge/cftr/

  The cystic fibrosis transmembrane conductance regulator (CFTR) is defective in cystic fibrosis (CF). This protein is a channel that sits on the surface of cells and transports chloride and other molecules, such as bicarbonate. Mutations in this gene lead to CF. Since the discovery of the CFTR gene in 1989, more than 2,500 mutations have been identified. […] Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a chloride channel located on the surface of certain epithelial cells. […] The CFTR protein is composed of 1,480 amino acids and is located on the surface of many cells in the body. The CFTR protein contains a single chain of amino acids that are grouped in five functional regions called domains. Two transmembrane domains (TMD1 and TMD2), two cytoplasmic nucleotide-binding domains (NBD1 and NBD2) and a regulatory (R) domain make up the CFTR protein. Each domain has a special function when it comes to transporting chloride through the cell surface. Therefore, mutations in different domains cause a range of CF symptoms depending on the extent that chloride transport is affected. Mutations in CFTR often affect the three-dimensional structure of the protein and prevent CFTR from reaching the membrane.

• #34 Basics of the CFTR Protein | Cystic Fibrosis Foundation

  https://www.cff.org/research-clinical-trials/basics-cftr-protein

  Researchers are still trying to learn more about the structure of the CFTR protein so that they can find new and better ways to help improve the function of the protein in people with CF. […] Because the 3-D shape of CFTR is so complex, it was not until early 2017 that the first high-resolution pictures were developed. These pictures have given researchers important clues about where drugs bind the protein, how they affect its function, and how to develop new CF therapies.

• #35 Cystic fibrosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700

  Cystic fibrosis is a disorder that damages your lungs, digestive tract and other organs. It’s an inherited disease caused by a defective gene that can be passed from generation to generation. Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with CF, they’re thick and sticky. Instead of acting as lubricants, these secretions plug up the tubes, ducts and airways in your body. […] Simply put, cystic fibrosis is a gene defect. A defect to this gene changes how a salt moves in and out of cells, resulting in thick, sticky mucus in the respiratory, digestive and reproductive systems. It’s an inherited condition. A child needs to inherit one copy of the mutated gene from each parent to develop cystic fibrosis. If they only inherit one copy from one parent, they won’t develop it. However, they will be a carrier of that mutated gene, so they could pass it along to their own children in the future.

• #36 Cystic fibrosis: Genetics and pathogenesis – UpToDate

  https://www.uptodate.com/contents/cystic-fibrosis-genetics-and-pathogenesis

  Cystic fibrosis (CF) is a multisystem disease affecting the lungs, digestive system, sweat glands, and reproductive tract. The primary abnormality is in transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines, and reproductive system. […] Over a highly variable time course ranging from months to decades after birth, individuals eventually develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure. […] The genetics and pathogenesis of CF are discussed here.

• #37 Basics of the CFTR Protein | Cystic Fibrosis Foundation

  https://www.cff.org/research-clinical-trials/basics-cftr-protein

  In people with CF, mutations in the CFTR gene can cause the following problems with the CFTR protein: It doesn’t work well, It isn’t produced in sufficient quantities, It is not produced at all. […] When any of these problems occur, the chloride ions are trapped inside the cell, and water is no longer attracted to the space outside the cell. When there is less water outside the cells, the mucus in the airways becomes dehydrated and thickens, causing it to flatten the cilia. […] Because the cilia can’t move properly, mucus gets stuck in the airways, making it difficult to breathe. In addition, germs caught in the mucus are no longer expelled from the airway, allowing them to multiply and cause infections. Thick mucus in the lungs and frequent airway infections are some of the most common problems people with CF face.

• #38 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. […] Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. […] The exact mechanism by which malfunctioning CFTR causes sinus disease is not completely understood. Chloride ions cannot be excreted, sodium is excessively absorbed, and water passively follows. This desiccates the mucosal surface and alters the viscosity of the normal mucus blanket, which alone can lead to obstruction of sinus ostia. […] Most deaths associated with cystic fibrosis result from progressive and end-stage lung disease. In individuals with cystic fibrosis, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation. Shortly after birth, many persons with cystic fibrosis acquire a lung infection, which incites an inflammatory response.

• #39 Cystic fibrosis – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/cystic-fibrosis/

  Mutated CFTR gene misfolded protein retention for degradation of the defective protein in the rough endoplasmic reticulum (rER) absence of ATP-gated chloride channel on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs). […] The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion). […] Defective ATP-gated chloride channel inability to transport intracellular Cl- across the cell membrane reduced secretion of Cl- and H2O accumulation of intracellular Cl- Na+ reabsorption (via ENaC); H2O reabsorption; formation of hyperviscous mucus accumulation of secretions and blockage of small passages of affected organs chronic inflammation and remodeling organ damage.

• #40 Cystic Fibrosis: The Mechanisms of Pathogenesis of an Inherited Lung Disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2430075/

  Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. […] CF lung disease is characterized by persistent bacterial infection that is usually acquired in childhood and maintained throughout the patient’s life. […] The F508 mutation results in abnormal biogenesis and premature degradation of CFTR protein by the cells quality control system and, as a result, there is a paucity/absence of CFTR in the apical membrane of CF epithelial cells. This results in a decreased permeability for chloride ions across CF epithelia. […] The key mechanisms in the development of CF lung disease are shown in Figure 1. In normal airway epithelia, CFTR-mediated Cl- secretion and ENaC mediated Na+ absorption are coordinated to maintain ASL at a depth that allows cilia to beat effectively and move the mucus blanket across the surface of the epithelium. The absence of CFTR protein and/or function in CF airway epithelium produces two defects in this process. First, the reduced permeability of CF epithelia to Cl- results in reduced Cl- secretion and hence less mass of salt on the apical surface. The result is a reduced driving force for water to enter the lumen. Secondly in the absence of CFTR, ENaC activity is unchecked, resulting in an unregulated and inappropriate absorption of salt from ASL. The overlying mucus blanket, consequently, becomes dehydrated and compresses the cilia, resulting in the arrest of MCC.

• #41 Cystic Fibrosis: The Mechanisms of Pathogenesis of an Inherited Lung Disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2430075/

  Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. […] CF lung disease is characterized by persistent bacterial infection that is usually acquired in childhood and maintained throughout the patient’s life. […] The F508 mutation results in abnormal biogenesis and premature degradation of CFTR protein by the cells quality control system and, as a result, there is a paucity/absence of CFTR in the apical membrane of CF epithelial cells. This results in a decreased permeability for chloride ions across CF epithelia. […] The key mechanisms in the development of CF lung disease are shown in Figure 1. In normal airway epithelia, CFTR-mediated Cl- secretion and ENaC mediated Na+ absorption are coordinated to maintain ASL at a depth that allows cilia to beat effectively and move the mucus blanket across the surface of the epithelium. The absence of CFTR protein and/or function in CF airway epithelium produces two defects in this process. First, the reduced permeability of CF epithelia to Cl- results in reduced Cl- secretion and hence less mass of salt on the apical surface. The result is a reduced driving force for water to enter the lumen. Secondly in the absence of CFTR, ENaC activity is unchecked, resulting in an unregulated and inappropriate absorption of salt from ASL. The overlying mucus blanket, consequently, becomes dehydrated and compresses the cilia, resulting in the arrest of MCC.

• #42 The Cellular Mechanism of CF: The Basics | Cystic Fibrosis News TodayEnvelope icon

  https://cysticfibrosisnewstoday.com/news/the-cellular-mechanism-of-cf-the-basics/

  Cystic fibrosis was ushered into the spotlight during President Barack Obama’s 2015 State of the Union Address as he highlighted the advances in CF therapy, which have served as a model for the President’s precision medicine initiative. […] The development of CF results from a misfolded or improperly functioning protein known as the cystic fibrosis conductance regulator (CFTR). The protein works in the apical membrane of epithelial cells in organs throughout the body as a chloride ion channel, which, as its name suggests, allows for the passage of chloride ions out of the cell. This movement attracts sodium ions across the cell membrane followed by a subsequent flow of water to the cell’s exterior. The passage of water is key because it hydrates and thins mucous so it can be properly cleared from organ passages, specifically in the lungs.

• #43 Cystic Fibrosis: The Mechanisms of Pathogenesis of an Inherited Lung Disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2430075/

  Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. […] CF lung disease is characterized by persistent bacterial infection that is usually acquired in childhood and maintained throughout the patient’s life. […] The F508 mutation results in abnormal biogenesis and premature degradation of CFTR protein by the cells quality control system and, as a result, there is a paucity/absence of CFTR in the apical membrane of CF epithelial cells. This results in a decreased permeability for chloride ions across CF epithelia. […] The key mechanisms in the development of CF lung disease are shown in Figure 1. In normal airway epithelia, CFTR-mediated Cl- secretion and ENaC mediated Na+ absorption are coordinated to maintain ASL at a depth that allows cilia to beat effectively and move the mucus blanket across the surface of the epithelium. The absence of CFTR protein and/or function in CF airway epithelium produces two defects in this process. First, the reduced permeability of CF epithelia to Cl- results in reduced Cl- secretion and hence less mass of salt on the apical surface. The result is a reduced driving force for water to enter the lumen. Secondly in the absence of CFTR, ENaC activity is unchecked, resulting in an unregulated and inappropriate absorption of salt from ASL. The overlying mucus blanket, consequently, becomes dehydrated and compresses the cilia, resulting in the arrest of MCC.

• #44 Cystic fibrosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700

  Cystic fibrosis is a disorder that damages your lungs, digestive tract and other organs. It’s an inherited disease caused by a defective gene that can be passed from generation to generation. Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with CF, they’re thick and sticky. Instead of acting as lubricants, these secretions plug up the tubes, ducts and airways in your body. […] Simply put, cystic fibrosis is a gene defect. A defect to this gene changes how a salt moves in and out of cells, resulting in thick, sticky mucus in the respiratory, digestive and reproductive systems. It’s an inherited condition. A child needs to inherit one copy of the mutated gene from each parent to develop cystic fibrosis. If they only inherit one copy from one parent, they won’t develop it. However, they will be a carrier of that mutated gene, so they could pass it along to their own children in the future.

• #45 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function). […] The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection. […] Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed. […] The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening. […] Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.

• #46 Cystic fibrosis lung environment and Pseudomonas aeruginosa infection | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-016-0339-5

  A major outcome of changes in lung environment is a shift of the balance between surviving microorganisms that enter the lung and the host defense mechanisms, which eventually result in conditions that favors the survival of the invading microbes together with a persistent yet ineffective immune responses. […] The CF respiratory tract is a highly diverse and complex ecosystem posing several challenges to inhabiting microorganisms in the process. […] The CFTR defect in CF changes the airway environment and anatomical parameters in the lower airways. […] The CF lower airways host diverse microorganisms and pathogens that are usually absent in healthy individuals. […] The mucociliary system consists of the cilia, the mucus layer covering the airway and the airway surface liquid (ASL) layer.

• #47 Cystic fibrosis lung environment and Pseudomonas aeruginosa infection | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-016-0339-5

  In CF, the defect in CFTR function leads to further absorption of isotonic liquid from ASL, leading to increase in thinning and viscosity of ASL. […] The ASL in CF lungs of children has been shown to be abnormally acidic. […] The airway microbiota in cystic fibrosis: a complex fungal and bacterial community-implications for therapeutic management. […] The pathogenic bacteria associated with CF include P. aeruginosa, H. influenzae, S. aureus and B. cepacia complex. […] The complex microbiome challenges our understanding of pulmonary exacerbation and succession of infecting organisms. […] The defect CFTR undermines first line of host defense in the pulmonary system and activates an inflammatory cascade independent of infectious stimuli. […] The repetitive cycle of inflammatory cell recruitment and unregulated immune cell activation causes tissue damage and leads to irreversible loss of lung function. […] The chronic infection with Pseudomonas aeruginosa presents itself as a dreadful threat and leads to a progressive decline in lung function.

• #48 Cystic fibrosis lung environment and Pseudomonas aeruginosa infection | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-016-0339-5

  In CF, the defect in CFTR function leads to further absorption of isotonic liquid from ASL, leading to increase in thinning and viscosity of ASL. […] The ASL in CF lungs of children has been shown to be abnormally acidic. […] The airway microbiota in cystic fibrosis: a complex fungal and bacterial community-implications for therapeutic management. […] The pathogenic bacteria associated with CF include P. aeruginosa, H. influenzae, S. aureus and B. cepacia complex. […] The complex microbiome challenges our understanding of pulmonary exacerbation and succession of infecting organisms. […] The defect CFTR undermines first line of host defense in the pulmonary system and activates an inflammatory cascade independent of infectious stimuli. […] The repetitive cycle of inflammatory cell recruitment and unregulated immune cell activation causes tissue damage and leads to irreversible loss of lung function. […] The chronic infection with Pseudomonas aeruginosa presents itself as a dreadful threat and leads to a progressive decline in lung function.

• #49 Newly described mechanism offers opportunities for treatment of cystic fibrosis – UMC Utrecht

  https://www.umcutrecht.nl/en/over-ons/nieuws/pers/newly-described-mechanism-offers-opportunities-for-treatment-of-cystic-fibrosis

  People with cystic fibrosis have a compromised defense against pathogens in the lungs, due to the accumulation of thick mucus in their lungs in which pathogens thrive. […] Cystic fibrosis (CF) is a hereditary disease that can be caused by many different mutations in a single gene in the DNA called CFTR. These mutations disrupt the function of the CFTR protein that is produced from this part of the DNA. Reduced CFTR function leads to changes in transport of salts and fluids in the cells that line the airway, leading to a different composition of the fluids in the airways and result in the classic thick and tough mucus that is a hallmark of the disease. […] But in addition to tough mucus, the airway surface fluid also becomes more acidic, which reduces bacterial killing by antimicrobial molecules made by airway cells.

• #50 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function). […] The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection. […] Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed. […] The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening. […] Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.

• #51 Cystic fibrosis lung environment and Pseudomonas aeruginosa infection | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-016-0339-5

  In CF, the defect in CFTR function leads to further absorption of isotonic liquid from ASL, leading to increase in thinning and viscosity of ASL. […] The ASL in CF lungs of children has been shown to be abnormally acidic. […] The airway microbiota in cystic fibrosis: a complex fungal and bacterial community-implications for therapeutic management. […] The pathogenic bacteria associated with CF include P. aeruginosa, H. influenzae, S. aureus and B. cepacia complex. […] The complex microbiome challenges our understanding of pulmonary exacerbation and succession of infecting organisms. […] The defect CFTR undermines first line of host defense in the pulmonary system and activates an inflammatory cascade independent of infectious stimuli. […] The repetitive cycle of inflammatory cell recruitment and unregulated immune cell activation causes tissue damage and leads to irreversible loss of lung function. […] The chronic infection with Pseudomonas aeruginosa presents itself as a dreadful threat and leads to a progressive decline in lung function.

• #52 The Cellular Mechanism of CF: The Basics | Cystic Fibrosis News TodayEnvelope icon

  https://cysticfibrosisnewstoday.com/news/the-cellular-mechanism-of-cf-the-basics/

  In CF, the absence, or dysfunction of this CFTR channel inhibits the flow of water and leaves mucous dehydrated and thickened, making it difficult to move with normal ciliary clearance. The immobilized, or stuck mucous then creates a nice, little niche for bacteria to grow, which gives rise to the classic manifestations of the disease including, chronic pulmonary infections, inflammation and decay of lung function. However, it should be noted that the thickened mucous plays a role in creating complications not only in the lung but other parts of the body, such as the sinuses, liver, pancreas, intestine and male reproductive tract. […] The structure of the CFTR, although seemingly abstract and uninteresting, is important because mutations in this gene, responsible for CF, can occur in any of these three regions resulting in two primary defects: a chloride channel, which is not in the proper shape and therefore cannot insert into the apical membrane, or a channel that does not open and close properly on the membrane. Either situation may result in reduced water flow and as previously described will create thick mucous. […] The continued identification of modifiers through this consortium serves to grow a greater understanding of the pathophysiology of the disease as well as identify potential targets for the development of future CF therapies.

• #53 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function). […] The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection. […] Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed. […] The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening. […] Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.

• #54 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function. […] In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency. […] Pancreatic disease results from a reduced volume of pancreatic secretion with low concentrations of bicarbonate, followed by retained and prematurely activated digestive proenzymes in pancreatic ducts, resulting in tissue destruction and fibrosis. […] Abnormally viscous secretions in the ducts of the pancreas, followed by loss of pancreatic exocrine function results in malnutrition and poor growth.

• #55 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. […] Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. […] The exact mechanism by which malfunctioning CFTR causes sinus disease is not completely understood. Chloride ions cannot be excreted, sodium is excessively absorbed, and water passively follows. This desiccates the mucosal surface and alters the viscosity of the normal mucus blanket, which alone can lead to obstruction of sinus ostia. […] Most deaths associated with cystic fibrosis result from progressive and end-stage lung disease. In individuals with cystic fibrosis, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation. Shortly after birth, many persons with cystic fibrosis acquire a lung infection, which incites an inflammatory response.

• #56 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. […] Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. […] Congenital absence of vas deferens may result in male infertility.

• #57 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  The airway surface liquid is an important component of the mucociliary escalator and also has key immunological functions. The effects of reduced airway surface liquid serve to impede mucus clearance. […] The altered lung environment provides a niche for bacterial growth with the biofilm mode of growth providing ideal conditions to protect bacteria from the host immune system and the actions of antibiotics. The pro-inflammatory cascade contributes to tissue damage. […] In the pancreas the pancreatic duct is usually occluded in-utero causing permanent damage to the exocrine pancreas rendering patients with CF pancreatic insufficient. […] In the gastrointestinal tract, the small intestine secretes viscous mucus which can cause bowel obstruction in-utero which can cause meconium ileus. […] In the biliary tree in-utero, CF can cause cholestasis which can result in neonatal jaundice. Later in life the same pathology can result in distal intestinal obstruction syndrome (DIOS) and CF-related liver disease (14% of patients).

• #58 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function. […] In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency. […] Pancreatic disease results from a reduced volume of pancreatic secretion with low concentrations of bicarbonate, followed by retained and prematurely activated digestive proenzymes in pancreatic ducts, resulting in tissue destruction and fibrosis. […] Abnormally viscous secretions in the ducts of the pancreas, followed by loss of pancreatic exocrine function results in malnutrition and poor growth.

• #59 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function. […] In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency. […] Pancreatic disease results from a reduced volume of pancreatic secretion with low concentrations of bicarbonate, followed by retained and prematurely activated digestive proenzymes in pancreatic ducts, resulting in tissue destruction and fibrosis. […] Abnormally viscous secretions in the ducts of the pancreas, followed by loss of pancreatic exocrine function results in malnutrition and poor growth.

• #60 Cystic fibrosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cystic_fibrosis_pathophysiology

  Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function. […] In cystic fibrosis, approximately 90% of patients present with exocrine pancreatic insufficiency. […] Pancreatic disease results from a reduced volume of pancreatic secretion with low concentrations of bicarbonate, followed by retained and prematurely activated digestive proenzymes in pancreatic ducts, resulting in tissue destruction and fibrosis. […] Abnormally viscous secretions in the ducts of the pancreas, followed by loss of pancreatic exocrine function results in malnutrition and poor growth.

• #61 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  The airway surface liquid is an important component of the mucociliary escalator and also has key immunological functions. The effects of reduced airway surface liquid serve to impede mucus clearance. […] The altered lung environment provides a niche for bacterial growth with the biofilm mode of growth providing ideal conditions to protect bacteria from the host immune system and the actions of antibiotics. The pro-inflammatory cascade contributes to tissue damage. […] In the pancreas the pancreatic duct is usually occluded in-utero causing permanent damage to the exocrine pancreas rendering patients with CF pancreatic insufficient. […] In the gastrointestinal tract, the small intestine secretes viscous mucus which can cause bowel obstruction in-utero which can cause meconium ileus. […] In the biliary tree in-utero, CF can cause cholestasis which can result in neonatal jaundice. Later in life the same pathology can result in distal intestinal obstruction syndrome (DIOS) and CF-related liver disease (14% of patients).

• #62 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. […] Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. […] Congenital absence of vas deferens may result in male infertility.

• #63 Pathology Pearls: Hepatobiliary Manifestations of Cystic Fibrosis | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/pathology-pearls/pathology-pearls-hepatobiliary-manifestations

  The main functions of this protein are to mediate transmembrane efflux of chloride ions and to regulate other ion channels and cellular processes. […] Consequently, dysfunction of CFTR leads to physicochemical changes in secretions within the tissues involved, complicated by ductal obstruction and secondary gland dysfunction. […] Specifically in the liver, CFTR protein is expressed on the apical membrane of cholangiocytes and regulates the content of water and electrolytes of bile. […] Loss of function results in production of thick, viscous bile with decreased alkalinity leading to impaired secretion, increased susceptibility to infections, and injury to the surrounding tissue from a combination of factors including direct bile-induced toxicity, associated release of free radicals, and secondary inflammation and fibrosis.

• #64 Pathology Pearls: Hepatobiliary Manifestations of Cystic Fibrosis | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/pathology-pearls/pathology-pearls-hepatobiliary-manifestations

  The main functions of this protein are to mediate transmembrane efflux of chloride ions and to regulate other ion channels and cellular processes. […] Consequently, dysfunction of CFTR leads to physicochemical changes in secretions within the tissues involved, complicated by ductal obstruction and secondary gland dysfunction. […] Specifically in the liver, CFTR protein is expressed on the apical membrane of cholangiocytes and regulates the content of water and electrolytes of bile. […] Loss of function results in production of thick, viscous bile with decreased alkalinity leading to impaired secretion, increased susceptibility to infections, and injury to the surrounding tissue from a combination of factors including direct bile-induced toxicity, associated release of free radicals, and secondary inflammation and fibrosis.

• #65 Cystic Fibrosis-Related Liver Disease (CFLD) < Hepar Lab

  https://medicine.yale.edu/lab/hepar/research/biliary/cystic/

  Cystic fibrosis is a common and severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates the secretion of chloride, bicarbonate and fluids in many secretory epithelia, including the epithelium of the bile ducts. […] In these patients, CFTR dysfunction in the biliary epithelium causes progressive chronic cholangitis that develops into biliary cirrhosis. […] Our studies uncovered an important correlation between CFTR and TLR4 signaling and demonstrated that CFTR deficiency alters the control of innate immunity in the biliary epithelium by reducing its tolerance to gut-derived endotoxins and favoring a stronger inflammatory response. […] Our hypothesis is that CFLD results from a complex interplay between genetic susceptibility and environmental factors and that changes in the intestinal microbiota, a leaky gut, and altered innate immune responses of the biliary epithelia constitute the milieu for the development and progression of CFLD. […] Current studies in the lab aim to understand the complex interplay between genetic susceptibility of the biliary epithelium and the causal role of the gut microbiota in the development and progression of CFLD.

• #66 Cystic Fibrosis-Related Liver Disease (CFLD) < Hepar Lab

  https://medicine.yale.edu/lab/hepar/research/biliary/cystic/

  Cystic fibrosis is a common and severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates the secretion of chloride, bicarbonate and fluids in many secretory epithelia, including the epithelium of the bile ducts. […] In these patients, CFTR dysfunction in the biliary epithelium causes progressive chronic cholangitis that develops into biliary cirrhosis. […] Our studies uncovered an important correlation between CFTR and TLR4 signaling and demonstrated that CFTR deficiency alters the control of innate immunity in the biliary epithelium by reducing its tolerance to gut-derived endotoxins and favoring a stronger inflammatory response. […] Our hypothesis is that CFLD results from a complex interplay between genetic susceptibility and environmental factors and that changes in the intestinal microbiota, a leaky gut, and altered innate immune responses of the biliary epithelia constitute the milieu for the development and progression of CFLD. […] Current studies in the lab aim to understand the complex interplay between genetic susceptibility of the biliary epithelium and the causal role of the gut microbiota in the development and progression of CFLD.

• #67 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #68 Cystic fibrosis transmembrane conductance regulator – Wikipedia

  https://en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

  Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with CF (cystic fibrosis). The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations of the CFTR gene affecting anion channel function lead to dysregulation of epithelial lining fluid (mucus) transport in the lung, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing vas deferens (spermatic cord) and epididymis appear to result from abnormal intraluminal secretions, causing congenital absence of the vas deferens and male infertility, and found associated with an imbalance of fatty acids.

• #69 Cystic fibrosis transmembrane conductance regulator – Wikipedia

  https://en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator

  Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with CF (cystic fibrosis). The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations of the CFTR gene affecting anion channel function lead to dysregulation of epithelial lining fluid (mucus) transport in the lung, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing vas deferens (spermatic cord) and epididymis appear to result from abnormal intraluminal secretions, causing congenital absence of the vas deferens and male infertility, and found associated with an imbalance of fatty acids.

• #70 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #71 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR function. […] The importance of the CFTR channel in macrophages was revealed in recent work that demonstrated that defective CFTR function is accompanied by impaired innate immune responses to specific infections. […] Autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. […] However, this process is impaired in CF patients and CF mice, as their cells exhibit limited autophagy activity. […] The mechanisms linking a malfunctioning ion channel function to the defective autophagy remains unclear. […] Thus, these novel data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.

• #72 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  The capacity of autophagy to clear intracellular pathogens such as bacteria, viruses, and parasites is collectively referred to as xenophagy. […] Autophagy has emerged as a central component of the innate and adaptive immune responses where it plays roles in direct and indirect killing of intracellular and extracellular pathogens, the generation of bactericidal peptides, and antigen presentation. […] Functions of autophagy that are compromised in CF include bacterial clearance, degradation of protein aggregates, and the elimination of dysfunctional mitochondria. […] Thus, the restoration of autophagy will have positive therapeutic effects in CF. […] The potential application of the TGM2 inhibitor cystamine in CF patients has recently been reviewed. […] Cystamine restores normal autophagy in CFTR-deficient cells and mouse models. […] This indicates that targeting p62 in CF is a promising approach to improve bacterial clearance and reduce inflammation in CF.

• #73 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR function. […] The importance of the CFTR channel in macrophages was revealed in recent work that demonstrated that defective CFTR function is accompanied by impaired innate immune responses to specific infections. […] Autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. […] However, this process is impaired in CF patients and CF mice, as their cells exhibit limited autophagy activity. […] The mechanisms linking a malfunctioning ion channel function to the defective autophagy remains unclear. […] Thus, these novel data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.

• #74 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  The previous commonly accepted hypothesis for CF pathology is the excessive secretion of thick mucus that remains in the lungs and is accompanied by impaired mucociliary clearance. […] An intriguing speculation arose from the specificity of organisms that tend to infect CF patients. […] We hypothesized that the susceptibility of CF patients to these infectious agents is due to weak autophagic activity since most of the organisms that tend to cause chronic infection in CF are controlled by autophagy in healthy cells. […] However, this process is impaired in CF patients and CF mice, as their macrophages and epithelial cells exhibit limited autophagic activity. […] The mechanisms linking a malfunctioning ion channel to the defective autophagy remains unclear. […] Hyper-inflammation and failure to clear infection is recognized as a leading cause of lung tissue destruction in CF that can be explained, at least in part, by incompetent autophagy machinery in cells with a dysfunctional CFTR channel.

• #75 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  The previous commonly accepted hypothesis for CF pathology is the excessive secretion of thick mucus that remains in the lungs and is accompanied by impaired mucociliary clearance. […] An intriguing speculation arose from the specificity of organisms that tend to infect CF patients. […] We hypothesized that the susceptibility of CF patients to these infectious agents is due to weak autophagic activity since most of the organisms that tend to cause chronic infection in CF are controlled by autophagy in healthy cells. […] However, this process is impaired in CF patients and CF mice, as their macrophages and epithelial cells exhibit limited autophagic activity. […] The mechanisms linking a malfunctioning ion channel to the defective autophagy remains unclear. […] Hyper-inflammation and failure to clear infection is recognized as a leading cause of lung tissue destruction in CF that can be explained, at least in part, by incompetent autophagy machinery in cells with a dysfunctional CFTR channel.

• #76 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  The capacity of autophagy to clear intracellular pathogens such as bacteria, viruses, and parasites is collectively referred to as xenophagy. […] Autophagy has emerged as a central component of the innate and adaptive immune responses where it plays roles in direct and indirect killing of intracellular and extracellular pathogens, the generation of bactericidal peptides, and antigen presentation. […] Functions of autophagy that are compromised in CF include bacterial clearance, degradation of protein aggregates, and the elimination of dysfunctional mitochondria. […] Thus, the restoration of autophagy will have positive therapeutic effects in CF. […] The potential application of the TGM2 inhibitor cystamine in CF patients has recently been reviewed. […] Cystamine restores normal autophagy in CFTR-deficient cells and mouse models. […] This indicates that targeting p62 in CF is a promising approach to improve bacterial clearance and reduce inflammation in CF.

• #77 Newly uncovered mechanism could drive next-generation cystic fibrosis treatments

  https://medicalxpress.com/news/2025-03-newly-uncovered-mechanism-generation-cystic.html

  A new study from The Hospital for Sick Children (SickKids) reveals the process underlying protein organization on cell membranes, a finding that could pave the way for innovative cystic fibrosis treatments. […] Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are around 700 known variants that cause CF, but current treatments address only a few, and none offer a cure. […] Rather than looking solely at the function of the CFTR protein, the study examined how CFTR proteins are organized on the cell membrane. In healthy children, the proteins form clusters, helping to regulate water and salt intake. In people with CF, those clusters are disrupted.

• #78 Newly uncovered mechanism could drive next-generation cystic fibrosis treatments

  https://medicalxpress.com/news/2025-03-newly-uncovered-mechanism-generation-cystic.html

  The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organization. […] Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies. […] These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF. […] Understanding CFTR as a phase-separating protein offers a new target for developing therapies, potentially benefiting patients unresponsive to current treatments and improving outcomes for all affected by the condition.

• #79 Newly uncovered mechanism could drive next-gen cystic fibrosis treatments

  https://www.sickkids.ca/en/news/archive/2025/newly-uncovered-mechanism-could-drive-next-gen-cystic-fibrosis-treatments/

  Protein clustering mechanism on the cell membrane presents a new therapeutic target for cystic fibrosis. […] Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations on the cystic fibrosis transmembrane conductance regulator (CFTR) gene. […] By studying protein organization, we’ve uncovered a brand-new avenue for developing therapeutics for cystic fibrosis, says Dr. Jonathon Ditlev, Scientist in the Molecular Medicine and Cell Systems Biology programs. […] Rather than looking solely at the function of the CFTR protein, the study, published in Proceedings of the National Academy of Sciences (PNAS), examined how CFTR proteins are organized on the cell membrane. […] The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organization and that Dr. Julie Forman-Kay, Program Head and Senior Scientist in the Molecular Medicine program and co-lead author of the paper, proposed might be relevant to CFTR in 2017.

• #80 Newly uncovered mechanism could drive next-generation cystic fibrosis treatments

  https://medicalxpress.com/news/2025-03-newly-uncovered-mechanism-generation-cystic.html

  The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organization. […] Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies. […] These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF. […] Understanding CFTR as a phase-separating protein offers a new target for developing therapies, potentially benefiting patients unresponsive to current treatments and improving outcomes for all affected by the condition.

• #81 Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060448

  Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. […] We identified three SNPs, one of which, the c.*1043AC, was located in a region predicted to bind miR-433 and miR-509-3p. […] The expression analysis demonstrated that the c.*1043AC increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043AC may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF. […] It is possible that such alleles bear mutations in regulatory sequences, like those at the 3 untranslated regions (UTR) that encode RNA sequences that bind specific microRNA (miRNA)s. These mutations may modify the affinity and thus the binding of a miRNA to the CFTR transcript, or may cause the appearance of novel target sites for miRNAs thus impairing the levels of CFTR expression, acting as causative mutations, or contributing to modulate the heterogeneous phenotypic expression of the disease.

• #82 Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060448

  The in silico prediction indicated that such mutation, the c.*1043AC, variant is located in the target site of two miRNAs, i.e., the miR-433 and the miR-509-3p, even if two previous studies did not consider such miRNAs as CFTR transcript modulators. The in vitro analysis demonstrated that the variant significantly enhances the affinity of the CFTR transcript for the miR-509-3p (that we demonstrated to inhibit CFTR expression). […] Our data suggest a new possible molecular mechanism in its pathogenesis. The presence of SNPs in the 3UTR may cause a variable phenotype, not only in terms of severity but also in terms of organ specificity. In particular, at least two different mechanisms lead to this variability. First, the aberrant expression of miRNAs, whose target sequence is present in the 3UTR of the CFTR gene, may decrease the expression of CFTR protein in specific organs. Secondly, as supported by our data, a decrease of CFTR protein expression can be caused by the presence of SNPs that increase the affinity for a specific miRNA in the 3UTR of the CFTR gene.

• #83 Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060448

  The in silico prediction indicated that such mutation, the c.*1043AC, variant is located in the target site of two miRNAs, i.e., the miR-433 and the miR-509-3p, even if two previous studies did not consider such miRNAs as CFTR transcript modulators. The in vitro analysis demonstrated that the variant significantly enhances the affinity of the CFTR transcript for the miR-509-3p (that we demonstrated to inhibit CFTR expression). […] Our data suggest a new possible molecular mechanism in its pathogenesis. The presence of SNPs in the 3UTR may cause a variable phenotype, not only in terms of severity but also in terms of organ specificity. In particular, at least two different mechanisms lead to this variability. First, the aberrant expression of miRNAs, whose target sequence is present in the 3UTR of the CFTR gene, may decrease the expression of CFTR protein in specific organs. Secondly, as supported by our data, a decrease of CFTR protein expression can be caused by the presence of SNPs that increase the affinity for a specific miRNA in the 3UTR of the CFTR gene.

• #84 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #85 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  The CFTR gene is located at 7q31.2. More than 1900 mutation have been identified of which F508del (deletion of three bases coding for phenylalanine at the 508th position) is the most common. […] Class II mutations contribute to protein processing abnormality leading to aberrant localization. […] Class III mutations contribute to protein regulation abnormalities leading to a decreased activity. […] Class IV mutations contribute to protein conduction abnormalities leading to altered frequency of ion flow. […] Class V mutations lead to a reduced amount of functional CFTR protein and class VI mutation cause an enhanced protein turnover. […] The current and future therapeutic targets are mainly focused on correcting structural and functional abnormalities of CFTR protein. […] A new group of drugs called CFTR modulators are available which are able to correct the basic defect in CF, i.e. CFTR protein itself though the exact mechanism is not fully elucidated.

• #86 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #87 7.6: Cystic Fibrosis in Humans – Biology LibreTexts

  https://bio.libretexts.org/Bookshelves/Genetics/Introduction_to_Genetics_(Singh)/07%3A_The_Central_Dogma_-_Mutations_and_Biochemical_Pathways/7.06%3A_Cystic_Fibrosis_in_Humans

  Cystic fibrosis (CF) is one of many diseases that geneticists have shown to be primarily caused by mutation in a single, well-characterized gene. The disease is due to a mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which was first identified by Lap-chee Tsui’s group at the University of Toronto (Tsui, 1995). Epithelial tissues in some organs rely on the CFTR protein to transport ions (especially Cl-) across their cell membranes. If there is insufficient activity of CFTR, an imbalance in ion concentration results, which disrupts the properties of the liquid layer that normally forms on the epithelial surface. In the lungs, this causes mucus to accumulate and can lead to infection. Defects in CFTR also affect pancreas, liver, intestines, and sweat glands all of which need this ion transport. Over one thousand different mutant alleles of CFTR have been described. Any mutation that prevents CFTR from sufficiently transporting ions can lead to cystic fibrosis (CF). Worldwide, the most common CFTR allele among CF patients is called F508 (delta-F508; or PHE508DEL), which is a deletion of three nucleotides that eliminates a phenylalanine from position 508 of the 1480 aa wild-type protein. Mutation F508 causes CFTR to be folded improperly in the endoplasmic reticulum (ER), which then prevents CFTR from reaching the cell membrane. CFTR is also notable because it is one of the well-characterized genetic diseases for which a drug has been developed that compensates for the effects of a specific mutation. The drug, Kalydeco (Ivacaftor), was approved by the FDA and Health Canada in 2012, decades after the CFTR gene was first mapped to DNA markers (in 1985) and cloned (in 1989). Kalydeco compensates for this mutation by binding to CFTR and holding it in an open conformation. […] The G551D mutation affects the ability of ATP to bind to CFTR and open the channel it for transport.

• #88 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  Orkambi acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies and enhances its activity eventually increasing the conductance of ions and fluid. […] Though the arrival of CFTR modulators have improved the CF management but there are still some limitation which include (a) non-significant response in F508del mutation heterozygotes by ivacaftor; (b) need to continue other daily symptomatic treatment; (c) interaction with CYP3A inducers and inhibitors; (d) side effects including elevated transaminases, cataract, oropharyngeal pain and URTI; (e) negligible benefit in 12 years old; (f) need of higher dose up to 600 mg (in case of lumacaftor); and (g) mutual interaction of lumacaftor and ivacaftor leading to increased metabolism of ivacaftor and need of a higher dose combination. […] Another promising approach is gene editing with the help of nucleases like zinc finger nucleases, transcription activator-like effector nuclease and especially CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 nuclease).

• #89 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  Orkambi acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies and enhances its activity eventually increasing the conductance of ions and fluid. […] Though the arrival of CFTR modulators have improved the CF management but there are still some limitation which include (a) non-significant response in F508del mutation heterozygotes by ivacaftor; (b) need to continue other daily symptomatic treatment; (c) interaction with CYP3A inducers and inhibitors; (d) side effects including elevated transaminases, cataract, oropharyngeal pain and URTI; (e) negligible benefit in 12 years old; (f) need of higher dose up to 600 mg (in case of lumacaftor); and (g) mutual interaction of lumacaftor and ivacaftor leading to increased metabolism of ivacaftor and need of a higher dose combination. […] Another promising approach is gene editing with the help of nucleases like zinc finger nucleases, transcription activator-like effector nuclease and especially CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 nuclease).

• #90 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  Orkambi acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies and enhances its activity eventually increasing the conductance of ions and fluid. […] Though the arrival of CFTR modulators have improved the CF management but there are still some limitation which include (a) non-significant response in F508del mutation heterozygotes by ivacaftor; (b) need to continue other daily symptomatic treatment; (c) interaction with CYP3A inducers and inhibitors; (d) side effects including elevated transaminases, cataract, oropharyngeal pain and URTI; (e) negligible benefit in 12 years old; (f) need of higher dose up to 600 mg (in case of lumacaftor); and (g) mutual interaction of lumacaftor and ivacaftor leading to increased metabolism of ivacaftor and need of a higher dose combination. […] Another promising approach is gene editing with the help of nucleases like zinc finger nucleases, transcription activator-like effector nuclease and especially CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 nuclease).

• #91 Cystic fibrosis: current therapeutic targets and future approaches | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1193-9

  Orkambi acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies and enhances its activity eventually increasing the conductance of ions and fluid. […] Though the arrival of CFTR modulators have improved the CF management but there are still some limitation which include (a) non-significant response in F508del mutation heterozygotes by ivacaftor; (b) need to continue other daily symptomatic treatment; (c) interaction with CYP3A inducers and inhibitors; (d) side effects including elevated transaminases, cataract, oropharyngeal pain and URTI; (e) negligible benefit in 12 years old; (f) need of higher dose up to 600 mg (in case of lumacaftor); and (g) mutual interaction of lumacaftor and ivacaftor leading to increased metabolism of ivacaftor and need of a higher dose combination. […] Another promising approach is gene editing with the help of nucleases like zinc finger nucleases, transcription activator-like effector nuclease and especially CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 nuclease).

• #92 Cystic fibrosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700

  Cystic fibrosis is a disorder that damages your lungs, digestive tract and other organs. It’s an inherited disease caused by a defective gene that can be passed from generation to generation. Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with CF, they’re thick and sticky. Instead of acting as lubricants, these secretions plug up the tubes, ducts and airways in your body. […] Simply put, cystic fibrosis is a gene defect. A defect to this gene changes how a salt moves in and out of cells, resulting in thick, sticky mucus in the respiratory, digestive and reproductive systems. It’s an inherited condition. A child needs to inherit one copy of the mutated gene from each parent to develop cystic fibrosis. If they only inherit one copy from one parent, they won’t develop it. However, they will be a carrier of that mutated gene, so they could pass it along to their own children in the future.

• #93 Cystic fibrosis: Genetics and pathogenesis – UpToDate

  https://www.uptodate.com/contents/cystic-fibrosis-genetics-and-pathogenesis

  Cystic fibrosis (CF) is a multisystem disease affecting the lungs, digestive system, sweat glands, and reproductive tract. The primary abnormality is in transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines, and reproductive system. […] Over a highly variable time course ranging from months to decades after birth, individuals eventually develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure. […] The genetics and pathogenesis of CF are discussed here.

• #94 Cystic Fibrosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK493206/

  The most commonly affected organs include the sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands. […] The result of this cascade is obstruction of the airways, which results in lung ventilation failure. […] In addition to acting as a chloride transport protein, other interactions of CFTR have been postulated. […] While not yet fully understood, modulation of CFTR protein in animal studies proved that inflammatory responses, maturational processing, nonchloride ion transport, and intracellular signaling are related to its function.

• #95 Cystic Fibrosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1001602-overview

  Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. […] Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. […] Congenital absence of vas deferens may result in male infertility.

• #96 Autophagy in Cystic Fibrosis Pathogenesis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/51976

  Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR function. […] The importance of the CFTR channel in macrophages was revealed in recent work that demonstrated that defective CFTR function is accompanied by impaired innate immune responses to specific infections. […] Autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. […] However, this process is impaired in CF patients and CF mice, as their cells exhibit limited autophagy activity. […] The mechanisms linking a malfunctioning ion channel function to the defective autophagy remains unclear. […] Thus, these novel data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF.

• #97 Newly uncovered mechanism could drive next-generation cystic fibrosis treatments

  https://medicalxpress.com/news/2025-03-newly-uncovered-mechanism-generation-cystic.html

  A new study from The Hospital for Sick Children (SickKids) reveals the process underlying protein organization on cell membranes, a finding that could pave the way for innovative cystic fibrosis treatments. […] Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are around 700 known variants that cause CF, but current treatments address only a few, and none offer a cure. […] Rather than looking solely at the function of the CFTR protein, the study examined how CFTR proteins are organized on the cell membrane. In healthy children, the proteins form clusters, helping to regulate water and salt intake. In people with CF, those clusters are disrupted.

• #98 Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060448

  Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. […] We identified three SNPs, one of which, the c.*1043AC, was located in a region predicted to bind miR-433 and miR-509-3p. […] The expression analysis demonstrated that the c.*1043AC increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043AC may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF. […] It is possible that such alleles bear mutations in regulatory sequences, like those at the 3 untranslated regions (UTR) that encode RNA sequences that bind specific microRNA (miRNA)s. These mutations may modify the affinity and thus the binding of a miRNA to the CFTR transcript, or may cause the appearance of novel target sites for miRNAs thus impairing the levels of CFTR expression, acting as causative mutations, or contributing to modulate the heterogeneous phenotypic expression of the disease.

• #99 Cystic Fibrosis- Pathophysiology -Managment- TeachMePaediatrics

  https://teachmepaediatrics.com/respiratory/lower-respiratory-tract/cystic-fibrosis/

  98% of men with CF are infertile due to a congenital absence of the vas deferens. […] CF is an autosomal recessive condition. […] Different organs have different sensitivity to loss of CFTR protein function, with the vas deferens particularly sensitive in contrast to the lungs, which are less sensitive. […] Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein made by the CFTR gene. […] Potentiators are CFTR modulators that hold the gate to the CFTR channel open so chloride can flow through the cell membrane. Correctors help the CFTR protein to form the right 3-D shape so that it is able to move or traffic to the cell surface.

• #100 The history, and the future, of cystic fibrosis | Royal Brompton & Harefield hospitals

  https://www.rbht.nhs.uk/blog/history-and-future-cystic-fibrosis

  Of the 2,000 CFTR gene mutations, about ten per cent are stop mutations. These can’t be treated with drugs because drugs work on the protein: with a stop mutation, you don’t make the protein in the first place. That’s now the focus for gene therapy. […] This new small molecule therapy is the first ground-breaking medicine which treats the basic defect and transform the lives of people with CF – it is the first time in my 30 years of working in CF there’s been anything like this. […] New therapies in development will continue to enhance the lives of people with CF and extend survival even further.

• #101 IJMS | Special Issue : Molecular Mechanisms and Pathophysiology of Cystic Fibrosis

  https://www.mdpi.com/journal/ijms/special_issues/YB08F7QQT2

  Cystic fibrosis (CF) is a multi-system disease caused by variants in the CF transmembrane conductance regulator (CFTR) gene. The resultant protein dysfunction results in a wide variety of pathological mechanisms causing multi system pathology. […] While CFTR protein modulators improve clinical outcomes in many people with CF (pwCF) and especially reduce aspects of airway pathology, the disease remains progressive, especially in pwCF, who had significant lung function decline before initiation of modulator therapy. Furthermore, many disease manifestations do not respond to CFTR modulator therapy resulting in ongoing morbidity. […] This special issue welcomes basic and translational research studies that focus on characterizing or exploring pathological processes that may have implications in future treatment and better understanding of disease processes in CF-associated disease manifestations. This issue will emphasize understanding of pathological mechanisms that underpin aging and long-term disease progression, pathological mechanisms in airway and non-airway disease processes, and novel or new understandings of CF pathological mechanisms in the post CFTR modulator era.

Zobacz więcej