Cystic fibrosis results from a non-functioning CFTR (cystic fibrosis transmembra
ID: 71996 • Letter: C
Question
Cystic fibrosis results from a non-functioning CFTR (cystic fibrosis transmembrane conductance receptor). Loss of function of the receptor results in altered epithelial salt and water transport due to an inability of CFTR to transport chloride ion (Cl-). This loss of transport function has multi-system impacts, leading to a variety of pathologies associated with CF.
a) One of the most common genetic mutations responsible for a defective CFTR is a 3 base pair deletion which results in the in-frame deletion of a phenylalanine residue. Apply your knowledge of the central dogma (i.e., from transcription!protein synthesis) and protein structure and function to explain how this deletion can result in a fully-synthesized CFTR which is inserted correctly into the epithelial membrane yet remains non-functional.
b) Loss of CFTR function in the lungs leads to production of extremely thick mucus (i.e., it is too low in water content). Based on your knowledge of cellular ion transport and the movement of water by osmosis, do you think that CFTR is no longer able to import or export Cl- (choose one)? Provide a rationale for your answer.
c) CF patients typically have difficulty performing moderate to heavy aerobic activities. Explain why this occurs by using your knowledge of the important link between cellular respiration and respiration (i.e., breathing).
d) Mutation of CFTR also has implications for the gastrointestinal and endocrine systems. Thickened mucus secretions within the pancreas impairs the ability to release important digestive enzymes. A thickening of pancreatic secretions is associated with poor growth and development. Apply your knowledge of the gastrointestinal system to explain the connection between decreased, thickened secretions and poor growth & development.
e) Thick mucus secretions in the pancreas may cause structural damage that is related to development of cystic fibrosis-related diabetes (CFRD). Explain diabetes and apply your knowledge of the endocrine functions of the pancreas to explain why CFRD develops.
Explanation / Answer
a) Deletion of phenylalanine residue from the N-terminal nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator (CFTR) disrupts its protein structure by not folding properly, it will eventually affects its function, and thus causes cystic fibrosis. The absence of this amino acid is responsible for defective CFTR assembly and channel gating.
b) In the case of malfunction CFTR, the channel is unable to move ions in and out freely, and thus Cl- and Na+ ions remain in the cell. Due to the lack of negative ions outside the cell, extracellular environment becomes hypotonic and water does not move outside the cell to dissolve mucus.
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