The Cystic fibrosis conductance regulator (CFTR) gene is made up of 250,000 DNA nucleotides located in human chromosome 7. This gene is not a continuous DNA sequence rather is made of 27 segments called exons. Synthesis of this proteins involves splicing of these exons which are translated to a chain of amino acids that join together to form the protein. The gene encodes for Cystic fibrosis conductance regulator protein that in located on the membrane cells of epithelial tissues such as lungs, pancreas, and gastrointestinal tract among others. The protein folds to its tertiary shape which is functional (Tsui and Dorfman, 2013, p. 1). Cystic fibrosis conductance regulator protein functions as a movement channel through which chloride and bicarbonate ions leave or enter the cell. Several genetic variations (mutations) have been identified in the gene due to environmental factors, inherited mutations, genetic changing and integration of factors which results to cystic fibrosis phenotype. Cystic fibrosis is a condition whereby the composition of the mucus layer lining the epithelial surfaces is affected (4). It also affects the salt concentration in the sweat due to disruption of ion transport hence the disorder is tested by ‘sweat test’.

The mutations that have been identified are deletions, splice site, nonsense and firmeshift that lead to either complete loss of function which is more severe disease or reduction in function causing a milder effect. These mutations have been grouped into six classes in relation to how they affect the CFTR protein as follows:

1. Class I: Shortened protein – This is where there is no complete translation of the protein sequence and the process ends prematurely. An example is W1282X mutation where the amino acid tryptophan in not inserted in that position leading to a short protein.
2. Class II: Protein fails to reach cell membrane – There is a deletion of phenylalanine amino acid at position 508 and the mutation is represented by ΔF508. This condition is present in 85 percent of CF patients in Europe.
3. Class III: Poor regulation of the ion channel – There is a nonsense mutation such as G551D where glycine (G) amino acid is replaced with Aspartate (D) amino acid.
4. Class IV: Chloride conductance is reduced – There is a nonsense mutation such as R117H mutation where Arginine amino acid, (R), is replaced by Histidine (H) at position 117.
5. Class V: Low amount of CFTR protein due to incorrect splicing of the CFTR gene – An example is 3120+1G>A Splice-site mutation in gene intron 16 gene.

The Classes I, II, and III produces a CFTR protein has complete lost its function while Class V and VI produces a protein with less activity hence milder effects of cystic fibrosis (8).

The CF phenotype is mainly determined by the type of CF genotype the individual acquires from their parents. However, genetic factors and environmental factors such as diet and therapeutic intervention influence the CF phenotype. A gene contains a pair of alleles normally referred to as genotype and is either homozygote (similar) or heterozygote (different). This genotype will determine the outcome of the trait (11). Some the phenotypes observed in CF patients include:

1. Homozygote of wild-type/wild-type combination will have no sign of CF disorder (Unaffected) while and homozygote of 58F/508F lead to severe lung disease and pancreatic insufficiency.
2. Homozygote of R117H/R117 will not affect the lung or pancreas but will affect the vas deferens causing congenital bilateral absence.
3. Heterozygote combination such as WT/ ∆508F and WT/3120+1 G>A will not cause CF disorder while ∆508F / W1204X compound heterozygote will lead to pancreas insufficiency but will not affect the lungs.
4. Mild lung disease and pancreatic insufficiency has been seen in compound heterozygote of R553X and W1316X while same combination of 591∆18 / E831X does not affect either lung or pancreas but causes nasal polyps.

Reference

Tsui, L. and Dorfman, R., 2013. The Cystic Fibrosis Gene: A Molecular Genetic Perspective.        Cold Spring Harbour Perspectives in Medicine, 3, (2), 1-16.

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