TeacherOfMedicine: Cystic fibrosis

Disease class: Lung diseases

This is an autosomal recessive genetic disease.

The name cystic fibrosis refers to the pathology seen in the pancreas of CF patients: cysts and fibrosis.

It is caused by a mutation in the gene CFTR (Cystic Fibrosis Transmembrane conductance Regulator).
In cystic fibrosis, the gene is dysfunctional in both the maternal and paternal chromosome (homozygous mutation).
When only one copy of the gene is dysfunctional (heterozygous mutation) there is no cystic fibrosis. These patients are known as carriers. However, heterozygous carriers have some functional deficiencies.
CTFR is on chromosome 7.
The most common CTFR mutation is called ΔF508. In the CTFR gene, there is a deletion of 3 nucleotides (one codon) at positions 507/508. In the CTFR protein, there is a deletion of one amino acid: phenylalanine (F). The protein product does not fold appropriately. It cannot be transported to the cell surface and it is degraded instead.
There are many other CTFR mutations which cause a loss of function in the CTFR protein.

CTFR is a protein which sits inside the cell membrane and crosses from the cell interior to the exterior (transmembrane).
CTFR functions as a cell channel. It is ATP-gated. When ATP binds to the protein, it changes the conformation. The CTFR channel facilitates the movement of chloride (Cl-) and thiocyanate ([SCN]−) ions through the cell membrane.

An epithelium is a thin tissue in the body. It is a barrier made of a row of cells. There are various cell junctions which can provide relatively tight or loose connections between cells.
Epithelial surfaces form the innermost lining of many cavities.
When CTFR is dysfunctional, there is dysregulation of ion transport between extracellular spaces and cell interior spaces.
In airways, there is inappropriate escape of sodium ions into epithelial cells. H2O molecules follow the sodium ions into the cells. This dehydrates the airway surface liquid, leaving a liquid with a higher proportion of mucus. The ASL becomes thicker and more viscous. Cilia are unable to adequately function in this liquid.

Small airways become obstructed in the respiratory tract. The mucus traps pathogens but the cilia cannot clear the mucus at a sufficient rate.
Chronic infections occur and recur in the respiratory tract. This causes inflammation.
With years of inflammation and trauma, the tissues of the respiratory tract degenerates.

Small ducts become obstructed in the pancreatic exocrine system.
There is insufficient secretion of pancreatic products into the digestive system, causing pancreatic exocrine insufficiency.
This also causes pancreatitis.
There is damage to the pancreatic tissues, which may progress to cystic fibrosis-related diabetes mellitus.

Small ducts become obstructed in the reproductive system.
There is insufficient passage of reproductive gland secretions, causing infertility (97% in males).

At least 1 in 30 Caucasians have one or two CFTRΔF508 alleles.
In the cystic fibrosis population, there is a 70% frequency of the CFTRΔF508 allele. The other 30% of alleles have different mutations, but these alleles are also dysfunctional.

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