What is Proteus Syndrome?
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Proteus syndrome is a rare genetic disorder that is characterized by abnormal and overgrowth of various types of tissues throughout the body. The disease is believed to be capable of affecting any type of tissue in the body.[1] The most common types of tissue affected is that of the skin, bone, and adipocytes. The disease also affects the right and left sides of the body differently[2], as can be seen in the images on the left. Additionally, cerebriform growths are often seen on the hands and feet of patients. Proteus syndrome is caused by a mutation in the AKT1 gene that causes a glutamate to lysine substitution at the 17th amino acid. |
AKT1 gene
The normal AKT1 gene and its products play a vital role in a number of different pathways. The AKT1 gene codes for a protein that is a kinase enzyme. This means that it can catalyze the transfer of a phosphate group from one molecule to another. This transfer is often used in the activation of other enzymes. Akt1 activation can lead to a number of different enzymes to be either activated or inhibited. Overall, this leads to an increase in cell survival, cell proliferation, and a decrease in apoptosis[3]. |
How does Proteus Syndrome occur?
Proteus syndrome occurs from a single nucleotide substitution in the AKT1 gene, which is located on chromosome 14. The specific mutation occurs at the 49th position of the gene and is a guanine to adenine substitution. The effect on the AKT1 protein is a substitution of lysine instead of glutamine at the 17th amino acid[4]. The substitution results in a gain-of-function mutation. The mutation also occurs in somatic cells[5], meaning that it does not affect every cell, but instead affects daughter cells of the cell in which the mutation occurred and creates a mosaic model, as is shown above.
Gap in knowledge
The role of Akt1 in adipocyte proliferation in the extremities remains unclear. In wild-type Akt1 adipocytes do not proliferate past the mature phase, while they go through excessive proliferation in Akt1 with the Proteus Syndrome mutation and the reason for this is poorly understood. It also remains unclear why exactly this excessive proliferation is seen so often in the extremities.
Cures/Treatments
There currently is no cure for Proteus Syndrome. However, a phase 0/1 clinical trial with the drug Miransertib has shown a decrease in the volume of cerebriform growths in patients with Proteus Syndrome[6]. Miransertib is an AKT1 inhibitor, which if effective at inhibiting Akt1 and is a very promising therapeutic treatment for Proteus Synndrome.
Learn More:
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison
Created by: Tanner Klaus [email protected] |
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References:
1. Keppler‐Noreuil, K. M., Lozier, J. N., Sapp, J. C., & Biesecker, L. G. (2017). Characterization of thrombosis in patients with Proteus syndrome. American Journal of Medical Genetics Part A, 173(9), 2359-2365.
2. Biesecker, L. (2006). The challenges of Proteus syndrome: diagnosis and management. European journal of human genetics, 14(11), 1151-1157.
3. Nitulescu, G. M., Van De Venter, M., Nitulescu, G., Ungurianu, A., Juzenas, P., Peng, Q., ... & Margina, D. (2018). The Akt pathway in oncology therapy and beyond. International journal of oncology, 53(6), 2319-2331.
4. Jamis-Dow, C. A., Turner, J., Biesecker, L. G., & Choyke, P. L. (2004). Radiologic manifestations of Proteus syndrome. Radiographics, 24(4), 1051-1068.
5. Lindhurst, M. J., Sapp, J. C., Teer, J. K., Johnston, J. J., Finn, E. M., Peters, K., ... & Biesecker, L. G. (2011). A mosaic activating mutation in AKT1 associated with the Proteus syndrome. New England Journal of Medicine, 365(7), 611-619.
6. Keppler-Noreuil, K. M., Sapp, J. C., Lindhurst, M. J., Darling, T. N., Burton-Akright, J., Bagheri, M., ... & Biesecker, L. G. (2019). Pharmacodynamic study of miransertib in individuals with Proteus syndrome. The American Journal of Human Genetics, 104(3), 484-491.
Image references:
https://www.nejm.org/doi/full/10.1056/nejmoa1104017
https://www.spandidos-publications.com/10.3892/ijo.2018.4597
https://www.remembryo.com/mosaic-embryo/
https://rarediseases.org/rare-diseases/proteus-syndrome/