@@ -110,14 +110,14 @@ export function Description() {
</figure>
</div>
<H4text="Function of CFTR"id="function-cftr"/>
<p>CFTR functions primarily as a chloride ion channel. It is responsible for transporting chloride ions (Cl⁻) across epithelial cell membranes<SupScrollLinklabel="13"/>{/*ehem20*/} . Here's how it works:</p>
<p>CFTR functions primarily as a chloride ion channel. It is responsible for transporting chloride ions (Cl⁻) across epithelial cell membranes. Here's how it works<SupScrollLinklabel="12"/>{/*ehem18*/}:</p>
<ol>
<li><b>Regulation by phosphorylation</b>: The R domain must first be phosphorylated by PKA to allow channel activation. This phosphorylation is often triggered by cyclic AMP (cAMP), a signaling molecule<SupScrollLinklabel="21"/>.</li>
<li><b>Opening the channel</b>: Once the R domain is phosphorylated, ATP binds to the NBDs, causing conformational changes that open the chloride channel<SupScrollLinklabel="12"/>{/*ehem18*/}.</li>
<li><b>Chloride transport</b>: With the channel open, chloride ions move from inside the cell to the outside. This movement of chloride helps draw water out of the cell, thinning mucus and maintaining proper hydration of the epithelial surfaces<SupScrollLinklabel="13"/>{/*ehem19*/}<SupScrollLinklabel="13"/>{/*ehem20*/}.</li>
<li><b>Regulation by phosphorylation</b>: The R domain must first be phosphorylated by PKA to allow channel activation. This phosphorylation is often triggered by cyclic AMP (cAMP), a signaling molecule.</li>
<li><b>Opening the channel</b>: Once the R domain is phosphorylated, ATP binds to the NBDs, causing conformational changes that open the chloride channel.</li>
<li><b>Chloride transport</b>: With the channel open, chloride ions move from inside the cell to the outside. This movement of chloride helps draw water out of the cell, thinning mucus and maintaining proper hydration of the epithelial surfaces.</li>
<li><b>Closing the channel</b>: Hydrolysis of ATP causes the channel to close after a certain period, tightly regulating chloride transport.</li>
</ol>
<p>CFTR plays a critical role in maintaining the fluid balance on the surfaces of tissues such as the airways, digestive tract and sweat glands. By allowing chloride ions to flow out of the cells, CFTR ensures that water follows, preventing the accumulation of thick, sticky mucus<SupScrollLinklabel="13"/>{/*ehem19*/}.</p>
<p>CFTR plays a critical role in maintaining the fluid balance on the surfaces of tissues such as the airways, digestive tract and sweat glands. By allowing chloride ions to flow out of the cells, CFTR ensures that water follows, preventing the accumulation of thick, sticky mucus.</p>
<H4text="CFTR in Cystic Fibrosis"id="CFTR-in-cftr"/>
<p>In the lungs, this water movement is crucial for maintaining a thin, slippery layer of mucus that can trap and remove particles like dust and bacteria. The mucus is then moved out of the lungs by the action of cilia, tiny hair-like structures on the surface of epithelial cells. When the CFTR protein is defective, as in Cystic Fibrosis, chloride cannot properly exit the cells. This disrupts the osmotic gradient, preventing water from entering the mucus. As a result, the mucus becomes thick and sticky, making it difficult to clear and creating an ideal environment for bacterial infections, which leads to chronic inflammation and lung damage over time.</p>
<p>In the intestines, CFTR regulates fluid secretion into the digestive tract, which is vital for the normal movement of digestive contents. Without proper CFTR function, water movement is reduced, leading to thickened digestive fluids, blockages, and impaired nutrient absorption. This contributes to malnutrition and other digestive complications in Cystic Fibrosis patients. </p>
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@@ -126,8 +126,11 @@ export function Description() {
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</Subesction>
<Subesctiontitle="F508del"id="Cystic Fibrosis3">
<p>More than 1,000 mutations in the CFTR gene are responsible for the development of Cystic Fibrosis. The most common variant is the F508del mutation, found in approximately 70% of affected individuals of Caucasian descent in Canada, Northern Europe, and the United States <SupScrollLinklabel="22"/> . It is estimated that around 90% of people with Cystic Fibrosis in Europe and those of European heritage carry at least one F508del allele <SupScrollLinklabel="23"/><sup>,</sup><SupScrollLinklabel="24"/>. Research suggests that this mutation originated in Western Europe at least 5,000 years ago <SupScrollLinklabel="23"/> .</p>
<p>The F508del mutation involves the deletion of three nucleotides, "CTT," at position 508, which removes a phenylalanine residue without causing a frameshift. This deletion impairs the kinetic and thermodynamic folding of the NBD1 domain <SupScrollLinklabel="24"/> . As a result, the CFTR protein not only misfolds but also experiences defects in trafficking and premature degradation, leading to a reduction in its surface expression <SupScrollLinklabel="25"/> . This specific mutation is particularly severe because it affects both the production and function of CFTR, resulting in a more aggressive disease course. Consequently, patients with the F508del mutation may respond better to CFTR modulators, which target these specific defects in protein folding and function.</p>
<p>More than 1,000 mutations in the CFTR gene are responsible for the development of Cystic Fibrosis. The most common variant is the F508del mutation, found in approximately 70% of affected individuals of Caucasian descent in Canada, Northern Europe, and the United States <SupScrollLinklabel="1"/>{/* ehem1 */}. It is estimated that around 90% of people with Cystic Fibrosis in Europe and those of European heritage carry at least one F508del allele <SupScrollLinklabel="2"/>{/* ehem23 */}<sup>,</sup><SupScrollLinklabel="9"/>{/* ehem24 */}. Research suggests that this mutation originated in Western Europe at least 5,000 years ago <SupScrollLinklabel="2"/>{/* ehem23 */}.</p>
<p>The F508del mutation involves the deletion of three nucleotides, "CTT," at position 508, which removes a phenylalanine
residue without causing a frameshift. This deletion impairs the kinetic and thermodynamic folding of the NBD1 domain
<SupScrollLinklabel="9"/>{/* ehem24 */}. As a result, the CFTR protein not only misfolds but also experiences defects in trafficking
and premature degradation, leading to a reduction in its surface expression <SupScrollLinklabel="16"/>{/* ehem25 */}. This specific mutation is particularly severe because it affects both the production and function of CFTR, resulting in a more aggressive disease course. Consequently, patients with the F508del mutation may respond better to CFTR modulators, which target these specific defects in protein folding and function.</p>
<Collapsibleid="statistical-distribution-collapsible"title="Statistical distribution of F508del mutations">
<p>In 2023, a comprehensive analysis was conducted to assess the distribution of mutations in the CFTR gene associated with Cystic Fibrosis (CF) worldwide. Data was sourced from two reputable databases: the <ahref="https://cftr.iurc.montp.inserm.fr/cgi-bin/variant_list.cgi"title="CFTR-database-1">CFTR Mutation Database</a> and the <ahref="https://cftr2.org/mutations_history"title="CFTR-database-2">CFTR2 Database</a>. </p>
<p>The results indicate the following distribution of CFTR mutation types and their frequencies in percent: </p>
