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Fahy JV, Dickey BF. Airway Mucus Function and Dysfunction: NEJM. New England Journal of Medicine. 2011 Mar 10 [accessed 2020 Oct 16]. https://www.nejm.org/doi/full/10.1056/NEJMra0910061

Farinha CM, Amaral MD. Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin. Molecular and cellular biology. 2005 Jun [accessed 2020 Oct 16]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140594/

Gadsby DC, Vergani P, Csanády L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. NCBI. 2006 Mar 23.

Lazrak A, Fu L, Bali V, Bartoszewski R, Rab A, Havasi V, Keiles S, Kappes J, Kumar R, Lefkowitz E, et al. The silent codon change I507-ATC->ATT contributes to the severity of the ΔF508 CFTR channel dysfunction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013 Nov [accessed 2020 Oct 16]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046180/

Saint-Criq V, Gray MA. Role of CFTR in epithelial physiology. Cellular and molecular life sciences : CMLS. 2017 Jan [accessed 2020 Oct 17]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209439/

Southern KW. ΔF508 in cystic fibrosis: willing but not able. Archives of Disease in Childhood. 1997 Mar 1 [accessed 2020 Oct 16]. http://dx.doi.org/10.1136/adc.76.3.278

Stanke F, Barneveld Avan, Hedtfeld S, Wölfl S, Becker T, Tümmler B. The CF-modifying gene EHF promotes p.Phe508del-CFTR residual function by altering protein glycosylation and trafficking in epithelial cells. Nature News. 2013 Oct 9 [accessed 2020 Oct 16]. https://www.nature.com/articles/ejhg2013209

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On the protein:

CFTR structure is monitored by quality control (QC) proteins, including two chaperones: calnexin and hsp70. In its normal form, the CFTR protein is "complexed with these chaperones in the endoplasmic reticulum but, during the maturation process, dissociates itself and is transported to the Golgi apparatus" (Southern, 1997).

Lacking a phenylalanine residue, the ΔF508 CFTR mutant is misfolded and does not dissociate from the chaperones. As a result, the protein is degraded through the ubiquitin-proteasome pathway and is thus absent from the cellular membrane (Farinha & Amaral, 2005).

On the phenotype:

The absence of the protein on the cellular membrane prevents the secretion of Cl−, leading to a lack of an osmotic gradient which itself prevents or slows down the secretion of water. The dehydrated mucus then "clogs ducts and collects in the lung where it fosters ultimately lethal bacterial infection” (Gadsby et al., 2006)

Other organs, such as the pancreas and the liver, are also impacted by mutation, which can lead to the development of conditions such as diabetes or cirrhosis.

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The CFTR gene codes for the cystic fibrosis transmembrane conductance regulator, a channel protein whose function is to transfer chloride anions (Cl−) into and out of epithelial cells. This transfer is necessary for the "normal function of epithelia such as those that line airways and the intestinal tract and ducts in the pancreas, testes and sweat glands" (Gadsby et al., 2006).

Mucus, an aqueous secretion that lies on the surface of epithelial cells, acts as a lubricant and is part of a protective mechanism against pathogens and subsequent infections. Its composition and structure can vary widely, being for example "thick and adherent to the epithelium in the gut, but thin and mobile in the airway" (Fahy & Dickey, 2011).

"Transcellular salt secretion is mainly controlled by Cl− exit across the apical membrane and this occurs predominantly via CFTR" (Saint-Criq & Gray, 2017), which also regulates other ion channels and transporters. Cl− transport "creates the driving force for Na⁺ movement across the epithelium and the increased salt concentration on the luminal surface generates an osmotic driving force for water to be secreted" (Saint-Criq & Gray, 2017). This secretion of water is necessary for the production of a thin mucus and an efficient "mucociliary clearance, the process that allows the removal of trapped particulate matter by the coordination of fluid secretion and ciliary beating" (Saint-Criq & Gray, 2017).

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ΔF508 is a frameshift mutation caused by the deletion of three base-pairs (CTT) from position 1521 to 1523 on exon 10 of the CFTR gene. (Stanke et al., 2013)

The deletion involves two codons: codon 507, which normally codes for isoleucyne, and codon 508, which normally codes for phenylalanine. One cytosine is removed from the last position on codon 507, and two thymidines are removed from the first positions on codon 508.

The result is a silent mutation for codon 507, as it is recombined with the thymidine remaining from codon 508. Indeed, the sequence changes from ATC to ATT, both coding for the same amino acid, isoleucyne. However, even though the change in codon 507 does not impact the amino acid added to the protein, it nonetheless "alters the mRNA structure and translation dynamics" (Lazrak et al., 2013). The 508 codon, on the other hand, is completely removed from the gene sequence, resulting in the absence of the corresponding phenylalanine in the CFTR protein and the misfolding of the latter (for more details, see the picture attached).

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Name: CFTR

Location: 7q31.2

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Symptoms:

Persistent coughing that produces thick mucus or phlegm

Frequent lung infections (such as pneumonia or bronchitis)

Wheezing or shortness of breath

Salty-tasting skin

Liver disease (such as jaundice or cirrhosis)

Inflammation and scarring of the pancreas which can prevent the effective production of insulin and result in cystic fibrosis related diabetes (CFRD)

Poor growth or weight gain

Constipation and diarrhea

Male infertility