cystic fibrosis Flashcards
what is cystic fibrosis?
A genetic autosomal recessive, systemic and multiorgan disease caused by defective ion transport
The most common lethal genetic autosomal recessive disease in the white population
Imbalance of fluid and electrolytes causing thick, sticky mucus and viscous secretions to accumulate in different organs
which population is CF more common in?
caucasian population
what is the life expectancy of CF
mid 40s
what does autosomal and recessive mean?
Autosomal: Refers to any of the chromosomes other than the sex-determining chromosomes
Recessive: not expressed unless both copies are present i.e., two copies of the mutation are needed to cause the disease.
Autosomal Dominant: A gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.
what is cystic fibrosis caused by?
Cystic fibrosis is caused by a mutation in a gene that encodes Cystic Fibrosis Transmembrane conductance Regulator: a chloride channel expressed in epithelial cells and other type of cells
CFTR is located in the apical membrane of secretory and absorptive epithelial cells of the pancreas, intestine, liver, airway, vas deferens and sweat glands
CFTR protein functions as a cyclic AMP-dependent chloride channel, a bicarbonate channel and as a modulator of other ion channels
what is CFTR ?
Conductance Regulator Protein Channel
and its structure
CFTR is a chloride channel expressed in epithelial cells and other type of cells that maintains salt, fluid, and pH homeostasis in various epithelial tissues
TWOCFTRmolecules line up in parallel, tail by tail, forming a pore in its center.
NBD (nucelotide binding domain) and RD (regulatory domain) are in the cytosol and the MD (membrane domain) form the pore of the channel. Both RD and NBD are involved in regulating the channel activity. RD is phosphorylated by a cAMP-dep kinase, NBDs bind to and hydrolase ATP providing energy to open and close the pore. Major function is regulating chloride conductance but CFTR plays other roles including regulation of sodium absorption
CFTRmutations can occur in the gene sequence that encodes any of the 5 protein domains. However, many mutations occur in the sequence that encodes NBD1, including theF508delmutation.
The location of theCFTRmutations can affect the formation or function of the CFTR protein.2
CFTR is a protein that is found in various cell types, including lung epithelium, submucosal glands, pancreas, liver, sweat ducts and reproductive tract
CFTR is located in the apical membrane of secretory and absorptive epithelial cells of the pancreas, intestine, liver, airway, vas deferens and sweat glands
what is CFTR ?
Conductance Regulator Protein Channel
and its structure
skip
CFTR is a chloride channel expressed in epithelial cells and other type of cells that maintains salt, fluid, and pH homeostasis in various epithelial tissues
TWOCFTRmolecules line up in parallel, tail by tail, forming a pore in its center.
NBD (nucelotide binding domain) and RD (regulatory domain) are in the cytosol and the MD (membrane domain) form the pore of the channel. Both RD and NBD are involved in regulating the channel activity. RD is phosphorylated by a cAMP-dep kinase, NBDs bind to and hydrolase ATP providing energy to open and close the pore. Major function is regulating chloride conductance but CFTR plays other roles including regulation of sodium absorption
CFTRmutations can occur in the gene sequence that encodes any of the 5 protein domains. However, many mutations occur in the sequence that encodes NBD1, including theF508delmutation.
The location of theCFTRmutations can affect the formation or function of the CFTR protein.2
CFTR is a protein that is found in various cell types, including lung epithelium, submucosal glands, pancreas, liver, sweat ducts and reproductive tract
CFTR is located in the apical membrane of secretory and absorptive epithelial cells of the pancreas, intestine, liver, airway, vas deferens and sweat glands
where is CFTR found and its role there:
Pancreas: It maintains a normal volume and pH of pancreatic secretions necessary for digestion of nutrients
Lungs. It regulates salt and water balance, thus contributes to normal hydration of airways mucociliary clearance
GI-tract. It regulates the balance of electrolytes and fluid thus GI normal hydration, appropriate pH and normal composition of intestinal secretions
CFTR is a protein that is found in various cell types, including lung epithelium, submucosal glands, pancreas, liver, sweat ducts and reproductive tract
CFTR is located in the apical membrane of secretory and absorptive epithelial cells of the pancreas, intestine, liver, airway, vas deferens and sweat glands
what can CF cause?
pulmonary disease pancreatic dysfunction infertility salty skin gastrointestinal symptoms
what is pulmonary disease?
clinical manifestation
Copious sputum production Persistent cough Reduced lung function Inflammation and tissue damage Chronic Airway Infections Predominant organisms H. influenzae S. aureus P. aeruginosa
Chronic lung disease is the dominating manifestation and main cause of morbidity and mortality for CF
what is pancreatic dysfunction?
2 types
Exocrine pancreatic insufficiency
Impaired enzyme secretion from pancreas and malnutrition
Endocrine pancreatic insufficiency
CF related diabetes mellitus (30% of patients over 25)
In CF, pancreatic secretions have lower fluid volumes and increased acidity within the pancreatic lumen which leads to precipitation of the protein rich secretions, causing plugging of small ducts, obstruction, and progressive damage to the pancreas
other clinical manifestation of CF?
Meconium ileus: 20% of babies with CF; however, meconium ileus can have other reasons than CF
Gastrointestinal Symptoms: thickened intestinal secretion, malabsorption, malnutrition, decreased gut motility
Salty-tasting skin
Infertility: congenital absence of the vas deferens
what can mutations do?
Reduce transcription OR translation
Affect traffinking to surface
Accelerate protein turnover
Cause loss of protein function
F508del class II mutation and CF
Thick, sticky mucous buildup flattens cilia
CFTR protein is made but cannot reach the cell surface. The mutant needs a corrector and a potentiator.
When a mutation causes an amino acid to be deleted or an incorrect amino acid to be added, the CFTR protein cannot form its correct 3-D shape and function properly. These mutations are considered to be protein processing mutations.
The most common CF mutation, F508del, is primarily considered to be a missense amino acid deletion and a Protein Processing Mutation. The F508del mutation removes a single amino acid from the CFTR protein. Without this, the CFTR protein cannot stay in the correct 3-D shape. The cell recognizes that the protein isn’t the right shape and disposes of it.
G551D class III mutation and CF
Thick, sticky mucous buildup flattens cilia
CFTR protein can reach the cell surface but is defective: channel opening and gating are compromised (doorman problem).
G551D glycine to aspartate is a ‘missense’ amino acid change mutation that results in defective channel gating.
A change in one of the amino acids of CFTR means that even though the protein makes the right 3-D shape, it doesn’t function as well as it should.
This type of gating mutation locks the gate in the closed position so that chloride cannot get through. The G551D mutation abolishes ATP-dependent gating, resulting in an open probability that is approximately 100-fold lower than that of wild-type channels
