The defective ATP7A gene involved in Menke's Disease (MD) contains 23 exons (coding regions) and the coding region encompasses 4500 bp. About 300 different types of mutations have been identified in the ATP7A gene (Moller & Horn, 2008). Here is an illustration of what the fully functional ATP7A protein looks like:
The receptor's main job is to be expressed in the cells of the intestines and transport Copper from the small intestines to the blood stream. ATP7A protein mutations result in a "loss of function" due to the impaired binding or metabolism of Copper (Nussbaum, McInnes, & Willard, 2016). It is also responsible for shuttling enzyme-bound copper from the golgi body to the cell membrane when the copper level is too high inside of the cells (Moller & Horn, 2008). MD can also be considered a "transportation defect", but generally there is never any copper available outside of the cell to get it into the cell, so a cell would not need to shuttle it out. Although, this mechanism may need to be investigated if a child with MD is being treated with copper injections.
Many of the mutations that cause severe MD are due to protein truncation and amino acid substitution that changes the structure and therefore the function of the protein. Unfortunately, the type of mutation does not necessarily correspond to the severity of the disease due to the complicated nature of gene expression (Moller, Mogensen & Horn, 2009). Here is a pie chart of the frequencies in which each type of mutation occurs in the ATP7A gene:
(Shomu's Biology, 2014)
Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2016). Genetics in medicine. Philadelphia, PA: Elsevier.
Shomu's Biology. (2015, March 24). Nonsense mutation [Video File]. Retrieved from
https://www.youtube.com/watch?v=HFKEEGhI1ro&t=110s
Simple Science. (2016, January 25). Genetic mutations - Part 2 - Splice site mutations [Video File]. Retrieved from https://www.youtube.com/watch?v=DJUQwuwFT5A
Fig. 1. Domain organization of the ATP7A protein. The positions and sequence motifs conserved among the family of ATPases are shown. (Moller, Mogensen & Horn, 2009, 1274)
The receptor's main job is to be expressed in the cells of the intestines and transport Copper from the small intestines to the blood stream. ATP7A protein mutations result in a "loss of function" due to the impaired binding or metabolism of Copper (Nussbaum, McInnes, & Willard, 2016). It is also responsible for shuttling enzyme-bound copper from the golgi body to the cell membrane when the copper level is too high inside of the cells (Moller & Horn, 2008). MD can also be considered a "transportation defect", but generally there is never any copper available outside of the cell to get it into the cell, so a cell would not need to shuttle it out. Although, this mechanism may need to be investigated if a child with MD is being treated with copper injections.
Many of the mutations that cause severe MD are due to protein truncation and amino acid substitution that changes the structure and therefore the function of the protein. Unfortunately, the type of mutation does not necessarily correspond to the severity of the disease due to the complicated nature of gene expression (Moller, Mogensen & Horn, 2009). Here is a pie chart of the frequencies in which each type of mutation occurs in the ATP7A gene:
Figure 2. Frequency of different types of
mutations identified in the ATP7A gene at the Kennedy Center. (Moller et al., 2009, 1274)
Over the course of taking this Healthcare Genetics course, I have needed visuals of how each gene mutation affects the protein. Here is a list of videos that illustrate each:
- Splice-site:
(Simple Science, 2016)
- Nonsense
(Shomu's Biology, 2014)
- Insertions and Deletions:
(AK Lectures, 2014)
- Missense:
(Biotech Review, 2014)
References
AK Lectures. (2014, September,
11). Insertions, deletions and frameshift mutations [Video
File]. Retrieved from https://www.youtube.com/watch?v=wv73LL6OaKU&t=16s
Biotech Review. (2014, March 14). Missense mutation. [Video File]. Retrieved from
Moller, L.B., & Horn, N. (2008, June 9). Mutation detection in the Menkes gene ATP7A using protein truncation test. Clinical Medicine Insights: Pathology, 1, 49-53. Retrieved from
Moller, L.B., Mogensen, M., & Horn, N. (2009, October). Molecular diagnosis of Menkes disease: Genotype-phenotype correlation. Biochimie, 91(10), 1273-1277. Retrieved from https://doi.org/10.1016/j.biochi.2009.05.011
Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2016). Genetics in medicine. Philadelphia, PA: Elsevier.
https://www.youtube.com/watch?v=HFKEEGhI1ro&t=110s
Simple Science. (2016, January 25). Genetic mutations - Part 2 - Splice site mutations [Video File]. Retrieved from https://www.youtube.com/watch?v=DJUQwuwFT5A
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