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The endoplasmin reticulum (ER) plays such an important role in the synthesis of proteins and lipids that any disturbance in its function may have severe or even fatal consequences.
Proteins and lipids synthesized in the endoplasmic reticulum (ER) are being transported inside the cell mostly in the form of transport vesicles. Defects in this intracellular transporting system result in various diseases. One of the examples of such disorders is cystic fibrosis (CF). CF is caused by misfolded proteins in the ER. People with CF lack a specific type of plasma membrane chloride channel (called cystic fibrosis transmembrane regulator – CFTR), which leads to the buildup of a thick mucus that compromises several organs, mainly the lungs and pancreas. This misfolded CFTR protein becomes trapped within the ER and is eventually degraded, making CF an insidious disorder with the average life span around 40 years of age.
CF is an inherited fatal disorder that develops due to the mutations in a gene encoding a chloride channel CFTR, mentioned above. This disrupts the metabolism of essential fatty acids – linoleic, linolenic and arachidonic. Dysfunction of CFTR translates into dehydrated thick secretions causing peripheral airway obstruction with mucus plugging. Highly viscous mucus present in people with CF prevents its purification from pathogens, and therefore bronchi become more prone to infections. As a result, the accumulation of viscous mucus leads to a breathing disorder. Due to the disruption in the formation and transportation of phospholipids, the structure of mitochondrial membranes changes, and this results in the development of a “peeling paint” dermatitis along with the symptoms of pulmonary disease, exocrine pancreatic insufficiency, and high sweat chloride concentrations. The main cause of morbidity and mortality in CF is due to a progressive decline in lung function characterized by reduced expiratory flow rates, impairment of respiratory mechanics and abnormal blood gas values. Moreover, children with CF show impaired ventilatory control associated with a decrease in the ventilatory response to carbon dioxide (CO2) and hypoxia. Blockade of the gastrointestinal tract, pancreas and liver by viscous mucus causes disorders of the GI system and poor absorption of nutrients. Together with other transport proteins of the apical and basolateral membranes of epithelial cells, the CFTR plays an essential role in fluid secretion, because it facilitate normal transportation of salts (in the form of Na + and Cl- ions), which creates an osmotic force for transferring water across membranes.