# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 2 Pathogenesis of Cystic Fibrosis (CF)  
### Mutation in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)  
The leading cause of CF is a genetic alteration in the CFTR [14; 15]. CFTR, an ABC transporter complex, is regulated by the phosphorylation of cAMP and intracellular ATP. It has multiple functions, some of which are still not completely defined [16; 17]. It is located on the apical side of the epithelial tissue in various parts of the body, including the lungs, where one of its primary roles is to function as a Cl\({}^{-}\) channel. It also maintains the transmembrane flow of other electrolytes like HCO3\({}^{-}\), Na\({}^{+}\), and potassium (K\({}^{+}\)) ions across the cell membrane, which aid in controlling the mucus viscosity of the airway epithelial cells [18; 19]. Therefore, a defect in the CFTR gene fundamentally affects the ion transport function of the CFTR protein, which reduces anion secretion and enhances the absorption of ENaC-mediated Na\({}^{+}\) ions in the airway [20].  
Several genetic mutations can lead to the development of CF. Based on [PERSON]'s classification [21], CFTR mutations are divided into seven classes (I to VII). In class I, nonsense and frameshift mutations, including G542X, R1162X, and W1282X, affect protein production by mediating premature transcription termination, which leads to the development of a protein with either missing amino acids or a new amino acid sequence. These unstable mRNA transcripts are more liable to degradation by a nonsense-mediated decay (NMD) mechanism [22]. Most of the CF mutations belong to class II, including R560T, A561E, R1066C, and N1303K [23; 24; 25; 26], as well as the most common F508 del that occurs on at least one allele in 90% of CF patients. Class II mutations affect the structural conformation of the corresponding CFTR protein. These misfolded proteins remain associated with chaperons and are ultimately recognized and subjected to the Endoplasmic Reticulum-Associated Degradation (ERAD) pathway [27].  
Typically, phosphorylation of the regulatory domain, ATP binding, and hydrolysis of the nucleotide-binding domains (NBD) controls the activity of the CFTR channel gating. Class III mutations, such as G551D, are located in NBD, and disrupt the regulation of the CFTR channel by restraining ATP binding to these domains, leading to a decline in channel transport activity [28]. Class IV mutations, including R117H, R334W, and R234P, affect the amino acids found in the channel pore, and cause a decrease in the channel's conductivity [29]. The influence of class V mutations, such as 3272-26A\(>\)G, is observed in the amount of normal CFTR protein produced. The protein level is significantly reduced due to a splicing mutation, which results in the generation of insufficient normal transcripts [30]. Class VI mutations, for instance c.120 del123, contribute to a reduction in surface retention and the stability of CFTR in the plasma membrane [31; 32]. Although the effect of class VII mutation is similar to that of class I since the CFTR protein is not formed, its severity is greater. Here, no mRNA is synthesized, owing to a large deletion in the CFTR, such as dele2,3(21 kb) [33]. Class VII mutations are untreatable, owing to the lack of any corrective therapy [21].