Cystic Fibrosis


Introduction


Cystic Fibrosis CF is an autosomal recessive disorder caused due to Defective chloride channel –Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in epithelial cells leading to excessive mucus in the lungs.

Autosomal recessive disorder means there should be two mutant alleles present to confer the disease. Both parents must be heterozygous carriers of the mutant CFTR gene for their children to be at risk of being affected or being carriers.


Importance of Understanding the Cystic Fibrosis


Cystic fibrosis a disorder due to mutation in the CFTR chloride channel, the disorder involves variety of mechanisms notably

  • The mutation disrupts the flow of (water) H2O and (Chloride ions) Clin and out of cells.
  • Mutation in the (Phenylalanine at 508th position) Phe508 that makes the CFTR protein unfit for binding to the sorting sequences.
  • The Disorder causes Complications in many physiological organ systems.
  • Cystic Fibrosis is also can be regarded as a disorder due to misfolding of the protein.

CFTR


CFTR also called ABCC7 is a transport protein that belongs to ABC (ATP Binding Cassette) Superfamily that includes several hundred transport proteins found in organisms ranging from bacteria to human.


Structure of CFTR:


CFTR has a structure similar to other ABC transport proteins. CFTR is a chloride channel, not a Pump. It has CFTR has two transmembrane T domains and two cytosolic A, or ATP-binding, domains. CFTR contains an additional R (regulatory) domain on the cytosolic face; R links the two homologous halves of the protein, creating an overall domain organization of T1–A1–R–T2–A2. CFTR is expressed in the apical plasma membranes of epithelial cells in the lungs, sweat glands, pancreas, and other tissues. CFTR protein is important for the reuptake of Cl into the cells of sweat glands lost by sweating.

The Cl− channel of CFTR is normally closed. Channel opening is activated by phosphorylation of the R domain by a protein kinase, which in turn is activated by an increase in cyclic AMP (cAMP). Opening of the channel also requires sequential binding of two ATP molecules to the two A domains.

Structure of CFTR


Mutations in CFTR


The mutation responsible for CF in 70% of cases results in deletion of Phe residue at position 508. The mutant protein folds incorrectly, causing it to be degraded in proteasomes. As a result, Cl− movement is reduced across the plasma membranes of epithelial cells that line the airways, digestive tract, exocrine glands (pancreas, sweat glands), bile ducts, and vas deferens. Less-common mutations, such as G551D (Gly551 changed to Asp), lead to the production of CFTR that is correctly folded and inserted into the membrane but is defective in Cl transfer.


Pathophysiology of Cystic Fibrosis


  • As previously mentioned CFTR is a channel protein that controls the flow of H2O and Clin and out of cells. Mutation in the CFTR leads to loss of function-blocking the flow of these ions out of the cell due to the blocked channel.
  • CFTR is found in cells that produce mucus, sweat, and digestive juices. Normally CFTR helps in the secretion of fluids that are thin and slippery( properties of mucus) but mutation caused secretions to become sticky and thick resulting in the secretions plug up in the tubes, ducts, and passageways especially in the lungs and pancreas.
  • The disease state is due to the absence of a CFTR channel rather than a defective channel: CFTR is synthesized as an integral membrane protein initially transported to the Endoplasmic Reticulum (ER) before its final transport to its functioning location-Plasma membrane of epithelial cells. For transport of CFTR to the epithelial cells CFTR has a diacidic sorting signal that binds to the sec24 of COPII vesicle for retrograde transport, a type of coated vesicle involved in the Protein targeting and the Sec24 is a coat protein present in it.  Deletion Mutation in the Phe508-(F508) causes changes in the formation of the cytosolic portion of the CFTR so that the signal is unable to bind to the Sec24.  Folded CFTR with the mutation can also function normally and thus the disease is due to the absence of the channel rather than a defective channel.
  • The formation and secretion of an amyloid-prone polypeptide called Serum Amyloid A (SAA) protein are increased in patients with cystic fibrosis. This protein, or fragments of it, deposits in the connective tissue of the spleen, kidney, and liver, and around the heart. People with this condition, known as secondary systemic amyloidosis, have a wide range of symptoms, depending on the organs initially affected. A variety of mutations in this protein lead to amyloid deposition concentrated around different tissues, thus producing different symptoms.

Complications


 Respiratory System Complications

  • Bronchiectasis- Damaged bronchial tubes,
  • Nasal polyps-Growth in the nose,
  • Hemoptysis-coughing up the blood,
  • Pneumothorax
  • Acute exacerbation.

 Digestive System Complications

  • Nutritional deficiency as the thick mucus blocks the tubes that carry digestive enzymes from pancreas to intestine, inhibiting nutrient absorption,
  • Diabetes mellitus,
  • Blocked bile duct,
  • Distal intestinal obstruction syndrome (DIOS).

 Reproductive System Complications

  • Infertility in men due to blockage in the vas deferens,
  • Infertility in females.

Other complications

  • Osteoporosis(thinning of bones),
  • Electrolyte imbalance and dehydration.

References