Question

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 (from transcription to 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.

Answer 1

CFTR - Cystic Fibrosis Transmembrane Conductance Regulator.

The CFTR is a transmembrane protein and chloride channel in the vertebrates. This protein is coded by the CFTR gene. This genes codes for an ABC class transporter ion-channel protein. This protein is involved in the conductance of chloride ions across the cell membranes of the epithelium.

The CFTR proteins act as a channel in the membranes of a type of cells that produce the digestive enzymes, mucus, silva, sweat, and saliva. As already mentioned, these proteins are involved in the transport of chloride ions across the membranes. This transport helps in controlling the water movement in cells. This is very much necessary for the synthesis of freely flowing, thin mucus.

The CFTR protein is also involved in controlling the function of other channel proteins, that are involved in the transport of sodium ions. This process is very important for the normal functioning of the lungs and pancreas.

Mutations in the CFTR gene

The mutation mentioned in this question is ΔF508 which accounts for 70% of the mutant CFTR genes. It is a frameshift mutation that results in the deletion of phenylalanine at position 508 of the CFTR protein. It is a class II mutation(Protein processing mutation).

When a CFTR protein is made up of all the correct amino acids, then it will form a stable 3D structure. However when an amino acid is missing due to any mutation, then the 3D structure will be disrupted and cannot function properly. So in this case without the phenylalanine at position 508, the CFTR cannot fold into its normal 3D structure. The cell recognizes this defective protein and disposes of it.

Apart from this, there are some other mutations occurring CFTR proteins:

• Protein production mutations(Class I)
• Gating mutations (Class III)
• Conductance mutations (Class IV)
• Insufficient protein mutations (Class V)