Cystic fibrosis CFTR defects

The mechanism by which cholera toxin causes secretory diarrhea is through continuous stimulation of the CFTR-regulated CL channel (Figure 12-15). In cystic fibrosis, CFTR defects cause the abolition of intestinal chloride secretion without affecting the absorptive capacity. In homozygous CF patients, the disease is eventually lethal (discussed earlier). In cholera infections, however, CFTR is overactivated with fluid and electrolyte losses that lead to... 

Cystic fibrosis, a disease of the Caucasian population, is associated with defective CL regulation and is essentially a disorder of epithehal cells (113,114). The defect arises at several levels in the CL ion transporter, ie, the cystic fibrosis transmembrane regulation (CFTR), and is associated with defective CL transport and defective processing, whereby the protein is not correctiy incorporated into the cell membrane. The most common mutation, affecting approximately 60% of patients, is termed F 608 and designates the loss of phenylalanine at this position. This mutation appears to be at least 50,000 years old, which suggests that its survival may have had evolutionary significance (115). 

The gene defective in cystic fibrosis codes for CFTR (cystic fibrosis transmembrane condnctance regulator), a membrane protein that pumps CP out of cells. If this CP pump is defective, CP ions remain in cells, which then take up water from the surrounding mucus by osmosis. The mucus thickens and accumulates in various organs, including the lungs, where its presence favors infections such as pneumonia. Left untreated, children with cystic fibrosis seldom survive past the age of 5 years. 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

The majority of cases of cystic fibrosis result from deletion of phenylalanine at position 508 (AF508), which interferes with proper protein folding and the posttranslational processing of oligosaccharide side chains. The abnormal chloride channel protein (CFTR) is degraded by the cytosolic proteasome complex rather than being translocated to the cell membrane. Other functional defects in CFTR protein that teaches the cell membrane may also contribute to the pathogenesis of cystic fibrosis. 

Cystic fibrosis is a life-threatening genetic disease caused by a dysfunctional cystic fibrosis transmembrane regulator, CFTR protein, which modulates salt and water transport into and out of cells. This ion-channel defect leads to poorly hydrated, thick, mucous secretions in the airways and severely impaired mucociliary func-... 

T Defects in protein folding may be the molecular basis for a wide range of human genetic disorders. For example, cystic fibrosis is caused by defects in a membrane-bound protein called cystic /ibrosis transmembrane conductance regulator (CFTR), which acts as a channel for chloride ions. The most common cystic... 

The ABC1 protein is a member of a large family of multidrug transporters, sometimes called ABC transporters because they all have ATP-binding cassettes they also have two transmembrane domains with six transmembrane helices (Chapter 11). These proteins actively transport a variety of ions, amino acids, vitamins, steroid hormones, and bile salts across plasma membranes. The CFTR protein that is defective in cystic fibrosis (see Box 11-3) is another member of this ABC family of multidrug transporters. 

A disease that results from a decrease in fluid and salt secretion by a transport protein referred to as the cystic fibrosis transmembrane conductance regulator (CFTR). As a result of this defect, secretion from the pancreas is blocked, and heavy, dehydrated mucus accumulates in the lungs, leading to chronic lung infections. 

Mucoviscidosis or cystic fibrosis (CF) is indeed one of the most common autosomal recessive diseases. It is characterized by the production of a viscous secretion in the excretory glands. Accordingly, pancreatic cystic fibrosis can be observed in the pancreatic area and cylindrical bronchiectases in the pulmonary area. The inspissation of bile and mucus leads to obstruction of the bile canaliculi and subsequently to cholestasis. The gene product is characterized as cystic fibrosis transmembrane regulator (CFTR). (252) The gene defect, which is located on chromosome 7, causes a disorder of the intracellular transport of chloride ions (probably also of chloride ion secretion) and thus triggers the occurrence of CF. The incidence of mucoviscidosis is about 1 2,000-4,500. 

The analysis of sweat for increased electrolyte concentration is used to confirm the diagnosis of cystic fibrosis (CF). CF is recognized as a syndrome with a wide spectrum of clinical presentations associated with a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR), a protein that normally regulates electrolyte transport across epithelial membranes. (For a more detailed discussion of CF, see Chapter 40.) Several hundred mutations of CFTR have been identified. Although mutational analysis is available, it is not informative in all cases, and the sweat test remains the standard for diagnostic testing. ... 

Plereditary (trypsinogen and inhibitory protein defects, cystic fibrosis membrane regulator [CFTR] defects)... 

Cystic fibrosis is the most common lethal autosomal recessive disease affecting the Caucasian population. It has a frequency of approximately 1 in 2500 and a carrier frequency of approximately 1 in 25. The protein affected is the cystic fibrosis transmembrane conductance regulator (CFTR), which is a chloride ion channel. There are over 1000 mutations that have been discovered in the CFTR gene and over 80 percent of these mutations lead to disease. The mutations lead to (1) defective or decreased protein production, (2) defective processing of the protein, (3) protein that is defective in the regulation of the chloride channel, or (4) defect in the transport of chloride ions. The most common mutation, a deletion of a phenylalanine residue at amino acid position 508 (AFjog), results in misfolding of the protein it consequently does not traffic to the membrane. 

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