Question

1. In cystic fibrosis one amino acid is missing in the CFTR protein. Explain why this mutant protein will not end up in the plasma membrane. (You may need to investigate the normal function of this CFTR gene)

2. Why might a mutation in the DNA NOT lead to an abnormally functioning protein?

3. Describe one genetic disorder in which a gene is mutated and leads to abnormal protein folding ( other than Huntington’s). In “your disorder”, name the gene mutated and how it affects the protein.

4. Research Huntington’s disease: Describe the mechanism of the disease and its relationship to protein folding. Cite your references.

Answer 1

Solutions

1. The CFTR gene is responsible for the production of the CFTR protein (cystic fibrosis transmembrane conductance regulator protein). The major function of this protein is to regulate the transport of charged particles across the cell membrane. The protein aids in the movement of chloride ions from inside the cell to outside the cell. Once outside, these ions attract water, which is required by the cilia (on lung cell surfaces) to clear the passage from mucus build-up. In people with mutated CFTR, the chloride ions do not move to the outside, and hence the cilia becomes devoid of water, leading to build-up of mucus.

Most of the mutations occurring in the CFTR genes (most common being deletion of Phe in 508^th position of the protein) lead to improper folding of the protein. Such proteins are detected by the cell and are quickly degraded. This is mediated by the ubiquitin-proteasome protein degradation assembly. Hence, these proteins never reach the plasma membrane

2. Not all bases in the DNA might code for a protein. If the mutation occurs in a region of DNA that is not part of a gene, then the effects might not be tangibly visible, since there will be no effect on final protein structure. However, mutations in a gene- region of DNA would lead to malfunctioning / improperly folded proteins.

3. An example is that of Sickle cell anemia (SCA). It is an inherited blood disorder that causes red blood cells to become misshapen and break down. It is mainly caused due to improper folding and clumping of the Haemoglobin protein in the RBC. This happens because of a substitution mutation in the Hb-gene, in which glutamate in the 6^th position of the beta-globin gene is replaced by valine. This leads to hydrophobic interaction between neighboring Hb molecules.

4. Huntington’s disease (HD) is a type of inherited condition in which nerve cells in the brain break down over time. It causes a variety of movement disorders, and impairments in daily activities. Additionally, cognitive and psychiatric disorders develop over time.
HD is an autosomal dominant disorder, and is caused by an inherited defect in a single gene (the HTT gene). The mutation in the gene causes DNA segment to have multiple CAG trinucleotide repeats. In people with HD, the CAG segment is repeated 36 to more than 120 times. The result is that the HD protein is abnormally long, which is then cut by the protein degradation machinery of the cell into smaller, toxic fragments that bind together and accumulate in neurons, and disrupt the normal functions of these cells. Eventual destruction of neurons lead to the above mentioned effects.