International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 20-32 http://medscipublisher.com/index.php/ijmms 21 2 Genetic and Molecular Mechanisms in Cystic Fibrosis 2.1 Description of CFTR protein function and its role in ion transport The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein functions primarily as a chloride channel in epithelial cells, playing a crucial role in the regulation of ion transport across cell membranes. CFTR is activated by phosphorylation through Protein Kinase A (PKA) and the binding of ATP to its Nucleotide-Binding Domains (NBDs), which facilitates the opening of the channel and the movement of chloride ions out of the cell (Carson et al., 1995; Wang et al., 2020). This chloride ion transport is essential for maintaining the balance of salt and water on epithelial surfaces, which is critical for the proper function of organs such as the lungs, pancreas, and intestines (Tamanini et al., 2021; Papi et al., 2022). In addition to chloride ions, CFTR also regulates the transport of bicarbonate ions, which is vital for maintaining pH balance in various tissues. The dysfunction of CFTR leads to impaired chloride and bicarbonate transport, resulting in the thickening of mucus and the disruption of normal epithelial function. This imbalance in ion transport is a hallmark of Cystic Fibrosis (CF) and contributes to the disease's characteristic symptoms, including chronic respiratory infections and pancreatic insufficiency (Maiuri et al., 2019; Wang et al., 2020). 2.2 Common CFTR mutations and their classification Cystic fibrosis is caused by mutations in the CFTR gene, with over 2 000 different mutations identified to date. These mutations are classified into six classes based on their impact on CFTR protein production and function. Class I mutations result in no CFTR protein production due to premature stop codons. Class II mutations, such as the common ΔF508 mutation, lead to defective protein folding and trafficking, causing the CFTR protein to be degraded before reaching the cell surface (Ramachandran et al., 2016; McCarron et al., 2020). Class III mutations affect the regulation of the CFTR channel, impairing its ability to open and close properly. Class IV mutations reduce the conductance of the CFTR channel, while Class V mutations decrease the amount of CFTR protein produced. Finally, Class VI mutations lead to increased turnover and degradation of the CFTR protein at the cell surface. Each class of mutation contributes to the varying severity of CF symptoms and influences the choice of therapeutic interventions (Carson et al., 1995; Ramachandran et al., 2016). 2.3 Molecular consequences of CFTR dysfunction The dysfunction of CFTR results in a cascade of molecular consequences that disrupt epithelial ion transport and mucus production. The impaired chloride and bicarbonate transport leads to the dehydration of mucus, making it thick and sticky. This thickened mucus obstructs airways and ducts, creating an environment conducive to chronic bacterial infections and inflammation, particularly in the lungs (Maiuri et al., 2019; Papi et al., 2022). The persistent infection and inflammation further damage the epithelial tissues, exacerbating respiratory and digestive symptoms (McCarron et al., 2020; Wang et al., 2020). Additionally, CFTR dysfunction affects other cellular processes, such as autophagy and proteostasis. The malfunctioning CFTR protein triggers the activation of transglutaminase-2 (TGM2) and the inactivation of the Beclin-1 (BECN1) complex, leading to impaired autophagy and a pro-inflammatory state. This "infernal trio" of CFTR inhibition, TGM2 activation, and BECN1 sequestration locks the cell in a cycle of inflammation and cellular stress, contributing to the progression of CF and its associated complications (Figure 1) (Maiuri et al., 2019). Therapeutic strategies aimed at correcting CFTR function or modulating these downstream effects are critical for managing CF and improving patient outcomes. 3 Pathophysiology of Cystic Fibrosis 3.1 Key affected systems: respiratory, gastrointestinal, endocrine, and immune Cystic Fibrosis (CF) is a multisystem disorder primarily affecting the respiratory, gastrointestinal, endocrine, and immune systems. The respiratory system is severely impacted due to the defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, leading to thick mucus accumulation, chronic bacterial infections, and persistent inflammation. This results in progressive lung damage and is the leading cause of morbidity and mortality in CF patients (Costantini et al., 2020; Mitri et al., 2020; Ghigo et al., 2021). The gastrointestinal system
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