Question

Pick one class of CFTR mutations and brainstorm 2 examples of specific mutations that could fall in the class you have chosen. Many versions of correct answers are possible for each class mutations. Use your understanding of how the cell works and propose 2 mutations. Explain how they will work. For example, class I mutations is associated with no CFTR protein being made. Think how could that happen.

Answer 1

Answer:

Cystic fibrosis is caused by mutations, or changes, in the CFTR gene. This gene provides the code that tells the body how to make the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The protein controls the salt and water balance in the lungs and other tissues. All people have two copies of the CFTR gene, and there must be mutations in both copies to cause CF. More than 1,700 mutations of the CFTR gene have been identified. Although some are common, others are rare and found in only a few people.

CF is caused by ∼2000 mutations in the CFTR gene with a wide range of disease severity, which is further influenced by modifier genes and by the environmental and socioeconomic status of patients. The first classification of CF mutations into four classes according to their primary biological defect was proposed by Welsh and Smith in a landmark paper. Currently, six major classes are distinguished -

Class I encompasses frameshift, splicing, or nonsense mutations that introduce premature termination codons (PTC), resulting in severely reduced or absent CFTR expression.

Class II mutations lead to misfolding, premature degradation by the endoplasmic reticulum (ER) quality-control system, and impaired protein biogenesis, severely reducing the number of CFTR molecules that reach the cell surface.

Class III mutations impair the regulation of the CFTR channel, resulting in abnormal gating characterized by a reduced open probability.

Class IV mutations alter the channel conductance by impeding the ion conduction pore, leading to a reduced unitary conductance.

Class V mutations do not change the conformation of the protein but alter its abundance by introducing promoter or splicing abnormalities.

Class VI mutations destabilize the channel in post-ER compartments and/or at the plasma membrane (PM), by reducing its conformational stability and/or generating additional internalization signals. This results in accelerated PM turnover and reduced apical PM expression.

Therefore, we pick one class of CFTR mutations is Class II and brainstorm 2 examples of specific mutations that could fall in this class we have choosen are:

Examples: (1) F508del and

(2) N1303K

How is CFTR work:-