What is the role of genetics in cystic fibrosis?

 

Cystic fibrosis is a disease that is inherited in an autosomal recessive manner. The gene responsible for cystic fibrosis was identified in 1989 as cystic fibrosis transmembrane-conductance regulator glycoprotein (CFTR gene) located on the long arm of chromosome No.7. The pathophysiology of cystic fibrosis (cystic fibrosis) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein-producing gene. The CFTR protein functions to regulate the movement of chloride and sodium ions across the epithelial cell membrane. When a mutation occurs in a gene copy, ion transport breaks down and results in a thick mucus buildup throughout the body, causing respiratory insufficiency along with multiple obstructions and other systemic disorders.

The combination of decreased mucociliary clearance and altered ion transport allows bacterial colonization of the respiratory tract, mainly Pseudomonas, Haemophilus influenza, and Staphylococcus aureus. This pathogen causes an overwhelming inflammatory response. Ultimately, chronic infection and this repeated inflammatory response can cause airway damage. The presence of the same CFTR protein in the pancreatic ducts and sweat glands in the skin also causes symptoms in this system.

Step-by-step explanation

Cystic fibrosis (cystic fibrosis) is a genetic disorder that affects most of the lung organs, as well as the pancreas, liver, kidneys, and intestines. Long-term problems with cystic fibrosis include difficulty breathing and coughing up mucus due to recurring lung infections. Cystic fibrosis is a disease that is inherited in an autosomal recessive manner. The gene responsible for cystic fibrosis was identified in 1989 as cystic fibrosis transmembrane-conductance regulator glycoprotein (CFTR gene) located on the long arm of chromosome No.7.Symptoms of cystic fibrosis arise due to inflammation and infection in the lungs and digestive system disorders such as prolonged cough, shortness of breath, excessive sputum production, diarrhea, malnutrition due to impaired absorption of nutrients, to disorders of the hepatobiliary system such as gallstones. Cystic fibrosis is a genetic and incurable disease. Therefore, management of cystic fibrosis only aims to treat symptoms and prevent further complications.

Scientists have found more than 1,700 different mutations in the CFTR gene that can cause cystic fibrosis. Over the years, scientists have used several different methods to group these mutations into different classes. The current classification system classifies mutations according to the problems they cause in the production of CFTR proteins:

1. Protein production mutation (class I)

2.Protein processing mutation (class II)

3. Gating mutation (class III)

4. Conduction mutation (class IV)

5. Insufficient protein mutation (class V)

The CFTR protein is a single polypeptide chain, containing 1480 amino acids, functions for cyclic AMP-regulated Cl-channels and regulates other ion channels. The fully processed form of CFTR is found on the plasma membrane in the normal epithelium. Biochemical studies indicate that the F508 mutation causes process breakdown and intracellular degradation of CFTR proteins. The absence of CFTR on the plasma membrane is central to molecular pathophysiology due to the F508 mutation and the class I-II mutation. Meanwhile, class III-IV mutations produce CFTR proteins that have been completely processed but do not function or have little function on the plasma membrane.

The CFTR gene makes proteins that control the transfer of salt and water inside and outside cells in the body. In cystic fibrosis patients, the gene does not work effectively. This results in thick and sticky mucus and very salty sweat which can be the main features of cystic fibrosis.

The pathophysiology of cystic fibrosis (cystic fibrosis) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein-producing gene. The CFTR protein functions to regulate the movement of chloride and sodium ions across the epithelial cell membrane. When a mutation occurs in a gene copy, ion transport breaks down and results in a thick mucus buildup throughout the body, causing respiratory insufficiency along with multiple obstructions and other systemic disorders.

The combination of decreased mucociliary clearance and altered ion transport allows bacterial colonization of the respiratory tract, mainly Pseudomonas, Haemophilus influenza, and Staphylococcus aureus. This pathogen causes an overwhelming inflammatory response. Ultimately, chronic infection and this repeated inflammatory response can cause airway damage. The presence of the same CFTR protein in the pancreatic ducts and sweat glands in the skin also causes symptoms in this system.

Respiratory tract damage

Recent theories suggest that defective ion transport causes dehydration in the airway epithelium, and thickening of the mucus. In airway epithelial cells, cilia exist in a layer known as airway surface liquid (ASL), which is between the apical surface of the cell and mucus. The flow of chloride ions from cells into the ASL layer is determined by ion channels such as CFTR. Apart from that, CFTR also blocks another channel called Epithelial Na + Channel (ENac). The ENac channel allows sodium ions to leave the ASL and enter the respiratory epithelium, so that if the CFTR is damaged, sodium flows freely from the ASL and into the cells.

When water follows sodium, the ASL depth will be depleted and cilia will remain in the mucosal layer. This results in mucosal thickening and periciliary fluid depletion resulting in mucus adhesion to the airway surface. Since the cilia cannot move effectively in a thick environment, mucociliary clearance is reduced and mucus buildup occurs. The accumulation of thicker, nutrient-rich mucus in the lungs allows bacteria to hide from the immune system, causing recurrent respiratory infections.

Mucus clearance is the primary innate defense of the airways against inhaled bacterial infection. Thick mucus fails to clear from the airways, both by means of the ciliary mechanism and by coughing. The lungs of a cystic fibrosis patient are usually infected with bacteria from an early age. Bacteria that collect in the small airways of the lungs, together with mucus, form a bacterial microenvironment known as a biofilm layer, which is difficult for immune cells and antibiotics to penetrate. Thick secretions and repeated persistent respiratory infections can gradually destroy lung tissue. The thickening of the airway walls as a result of the remodeling process will make the infection more difficult to eradicate.

Gastrointestinal Damage

The effects of cystic fibrosis on the gastrointestinal tract are : In the exocrine function of the pancreas, the absence of CFTR Channel Cl- on the apical membrane of the pancreatic duct epithelium limits the apical function of the Cl-HCO3- membrane to secrete bicarbonate and Na + (through passive processing) into the duct. Failure to secrete Na +, HCO3- and water will lead to enzyme retention in the pancreas, ultimately leading to complete destruction of all remaining pancreatic tissue. Damage to the pancreas causes absorption of carbohydrates, proteins, fats, and fat soluble vitamins such as vitamins A, D, E, K due to the absence of enzymes such as lipase, trypsin, and amylase, so that malnutrition can occur.

Cystic fibrosis of the intestinal epithelium causes the secretion of water and Cl- to decrease, thereby failing to secrete mucin and macromolecules from intestinal crypts. CFTR-mediated fluid secretion may be exacerbated by the absorption of excess fluid, indicating abnormalities in Na + absorption regulation mediated by Na + channels and possibly other Na + transporters, eg Na + -H + ion pumps. Both of these dysfunctions cause dryness of the intestinal lumen contents and small and large bowel obstruction.

Cystic fibrosis of the hepatobiliary system results in accumulation of Cl- salts in the hepatic duct, and excessive water secretion leading to thickening of the biliary secretory tract. This can lead to focal biliary cirrhosis. Bile duct proliferation occurs in about 25-30% of patients with cystic fibrosis. The inability of the bile gland epithelium affected by cystic fibrosis to secrete bile salts and water can lead to choleocystitis and cholelithiasis.