Question

As Cystic Fibrosis affects the Golgi Apparatus, what are some specific treatments that attack mutation in the Golgi Apparatus?

Answer 1

Cystic fibrosis is an autosomal recessive disorder.

Chromosome affected - 7 (autosome)

Pathophysiology-

This disease is characterized by a defect in the cystic fibrosis transmembrane regulator (CFTR) protein

Functions of the CFTR

1. CFTR is a protein situated on the apical surface of the plasma membrane.
2. It is a chloride channel. It pushes chloride out of the cells and into the interstitium.
3. It also regulates the function of other channels like the epithelial sodium channels and other rectifiers chloride channels.

The mutations in the CFTR gene can cause:-

• No production of CFTR protein ( Mutations -R553X, W1282, G542X)
• Reduced the quantity of CFTR [ Mutations - F508del (most common), N1303K]
• Reduce the transport of chloride ( Mutation - R117H,)

F508del mutation is the commonest mutation seen with Cystic fibrosis. This reduces the number of CFTR protein. This has the following effect

1. the chloride efflux from the cell is reduced
2. Hypofunctioning CFTR protein affects the epithelial sodium channels as well.As a result, they excessively absorb sodium from the interstitium into the cell.
3. Decreased Chloride secretion and excessive sodium absorption lead to excessive water absorption.
4. As a result, a thick mucus is produced. This thick mucus reduces the ciliary function.

Before we learn about the drugs that affect the Golgi apparatus, let us acquaint ourself with a few facts:

1. Due to genetic defects in the CFTR gene, a defective CFTR protein is produced.
2. The defective CFTR protein is misfolded (tertiary structure of the protein).
3. This misfolded gene is recognized by the endoplasmic reticulum and destroyed.
4. As a result, the amount of CFTR protein reaching the cell surface is less.
5. Less number of CFTR protein leads to hypo-functioning of the protein.

. There are few drugs that help to over come this problem. These drugs ferry the defective (misfolded) CFTR protein from the endoplasmic reticulum to the cell surface. They protect them from getting destroyed by the endoplasmic- reticulum. They are called CFTR correctors

Examples of CFTR correctors are

1. Lumacaftor
2. Tezacaftor

Both these drugs are used in combination with ivacaftor.