1. In cystic fibrosis one amino acid is missing in the CFTR protein. Explain why
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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.
Explanation / Answer
1. ANS: Cystic Fibrosis is caused by a defect in Cystic fibrosis transmembrane conductance regulator (CFTR) gene whose function is to control the entry and exit of chloride ions into and from our body's cells. Thus a defective CFTR cannot produce a proper protein causing CF. Cystic Fibrosis (CF) is a genetically-inherited disease which is autosomal recessive in nature that primarily affects the lungs. Other organs that get affected are liver, kidney, pancreas and intestine. Lung infections due to mucus-clogged airways result in breathing problems. In case of pancreas, the secreted mucus does not allow the release of the important digestive enzymes needed by the body to breakdown food and absorb vital nutrients. Clubbing of fingers and toes, affected growth, infection in sinus include the other symptoms. Till now, no cure has been developed for this disease.
Mutations at the 508th position (DF508) in the CFTR gene located on human chromosome 7 cause CF symptoms. Thousands of mutations are possible that affect the CFTR gene in many ways possible. The most common mutation of CFTR is a deletion mutation at position 508 of the sequence where 3 DNA nucleotides are deleted causing leading to deletion of phenylalanine. Other mutations also affect the CFTR gene which may or may not have symptoms of CF, but have some other mild effects. Such diseases may be called "CF-related diseases".
2. ANS: Neutral mutations are changes in DNA sequence that are neither beneficial nor detrimental to the ability of an organism to survive and reproduce. The amino acid can do change as long as it does not affect the protein activity/function. The mutation may be silent/non-synonymous (no change in protein), or synonymous (change in protein sequence, but no effect).
Ex: Bovine and human insulin, while differing in amino acid sequence are still able to perform the same function. The amino acid substitutions between species were seen therefore to be neutral or not impactful to the function of the protein. Neutral mutation and the neutral theory of molecular evolution are not separate from natural selection but add to Darwin's original thoughts. Mutations can give an advantage, create a disadvantage, or make no measurable difference to an organism's survival.
3. ANS: The most common diseases which occur by the accumulation of misfolded proteins are Parkinson’s disease and Alzheimer's disease and both the diseases are also called as amyloid diseases. Parkinson's disease is a neurological disease common to elderly individuals and this disease was caused by the mutation in protein synuclein synthesis, folding and degradation is affected and results in the accumulation of misfolded proteins and forms aggregates, and abnormal tendency of proteins to aggregation results into misfolding. As a result, the neurons of the substantia nigra can no longer produce dopamine. These Lewy Bodies have a target shaped appearance. They are composed of alpha synuclein. By the pathological increase in the intracellular concentrations imbalances protein and leads to duplications (mutations) of the amyloidogenic gene changes the protein's amino acid sequence.
4. ANS: Huntington's disease is a neurodegerative disorder that occurs during middle to late adult life. This disease is caused by mutation in HD (HTT) gene on chromosome 4. This gene codes for Huntingtin protein. Towards the beginning of this gene there is a three letter codon sequence, CAG which gets repeated few times. CAG codes for amino acid, glutamine. Here there is progressive loss of nerve cells in the brain leading to dementia.
Huntingtin protein is found throughout the body but it interacts with proteins of bain only. So an altered protein can be disruptive for the nerve cells. As glutamine is a polar amino acid, its expansion causes formation of links in the protein. Thus instead of folding into a functional protein it gets entangles and forms rigid bodies called aggregates. These fibrous aggregates can hamper the nerve cell functioning by enticing the crucial regulatory factors. Polyexpansion of glutamine signals the cells to recruit proteases like Caspases which breaks this protein into smaller fragments which forms aggregates and hence hampers the functioning of this protein and also it can enter nucleus and hamper the cell's functioning.
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