A review of cystic fibrosis: Basic and clinical aspects

Abstract

Cystic fibrosis (CF), a monogenic disease, is the most common life-shortening autosomal recessive disease that afflicts people of Northern European descent. It was first formally reported to the worldwide medical community in 1949. According to the American Cystic Fibrosis Foundation patient registry, there are currently more than 30 000 CF patients in the United States and more than 70 000 CF patients throughout the world. Globally, about 1000 cases of CF are newly diagnosed every year, with over 75% of CF patients diagnosed at 2 years of age and an average age at diagnosis of about 3 years of age. CF incidence rates vary around the world, but rates as high as 1 in 2000 to 3000 live births are associated with Caucasian populations with Northern European ancestry. The median predicted survival time of CF patients in the United States is approximately 47.4 years (95% CI, 44.2-50.3) according to the Cystic Fibrosis Foundation 2018 Registry Report. However, epidemiological data on CF prevalence in China have not yet been reported, aside from observations that the genotypic spectrum of Chinese CF varies widely among resident subpopulations based on their geographical and ethnic origins.Numerous animal CF models have been established based on specific types of human CFTR mutations, but models differ in their effectiveness in mirroring features of human CF-specific disease.For example, the mouse CF model differs markedly from human CF at the pathological level, while at the molecular level CFTR genes of pig and human are highly homologous, but their corresponding CFTR protein structures and functions are vastly different. At present, ferret and rabbit CF models hold promise as human CF models, but additional models based on other species should also be evaluated.Meanwhile, the introduction of human CFTR genes harboring CFTR mutations into genomes of animals holds promise as a strategy for creating better animal models for human CF. Nevertheless, current animal models each have their own unique features that are useful for studying particular aspects of human CF disease, as described below.

CFTR and Gastrointestinal Cancers: An Update

“…This was further confirmed by histological analysis [ 28 ]. In patients without CF, the downregulation of CFTR expression was reported in a study by Chen et al, who studied abnormally methylated differentially expressed genes in HCC, using gene expression profiles available from the Gene Expression Omnibus (GEO) that identified CFTR as a hypermethylated, low expressing hub gene in HCC [ 3 ]. Similar downregulation of CFTR by promoter hypermethylation was reported by Moribe et al in a study of 25 HCC samples compared with normal control tissues [ 29 ].…”

“…Mutations in the CFTR gene fall into six basic classes. The most common pathogenic mutant form of CFTR is designated as F508del (a phenylalanine residue at site 508 is deleted) and this mutation is most common among Caucasians of northern European descent [ 3 ].…”

Cystic fibrosis: a comprehensive review

“…Table 2 comprises the present acknowledged seven types of mutations. Class I mutations are usually caused by nonsense, frameshift, or splicing alterations, having as a consequence the premature termination of codons (PTCs) and a truncated CFTR protein (Chen et al, 2021). PTCs can significantly reduce mutant mRNAs' half-lives through the nonsense-mediated mRNA decay (NMD) pathway but also via alteration of the pre-mRNA splicing pattern, thus leading to a small amount of non-functional CFTR protein (Nissim-Rafinia, 2007).…”

“…Class III mutations are associated with a reduced activity of the Clchannel despite exhibiting adequate levels of ATP. Moreover, a wide range of mutations can modifiy the NBD-ATP binding regions, whereas some mutant variants can retain a certain degree of sensitivity to nucleoid binding (Chen et al, 2021). Class IV mutations causes a diminished rate of the ion flow and duration of the channel opening even though the chloride currents are still generated in response to cAMP stimulation (Chen et al, 2021).…”

“…Moreover, a wide range of mutations can modifiy the NBD-ATP binding regions, whereas some mutant variants can retain a certain degree of sensitivity to nucleoid binding (Chen et al, 2021). Class IV mutations causes a diminished rate of the ion flow and duration of the channel opening even though the chloride currents are still generated in response to cAMP stimulation (Chen et al, 2021). Thus, both mutation classes III and IV can be associated with the production of the CFTR protein which can be processed, transported and inserted into the apical surface of cells but displays a dysfunctional conductance (Nissim-Rafinia, 2007).…”