Saturday, June 30, 2012

Genetic discovery explains variety of brain disorders

Development of an organism, construction of tissues and even the onset of disease: it all starts with genetics. Genes provide the blueprint for proteins, which in turn form the foundations of all structures. Finding genetic modifications, or mutations, often tell us something about how things go wrong, as a disturbed blueprint leads to malfunctioning proteins and thus disease. Scientists from Seattle Children's Research Institute have found a series of mutations in genes that explain a variety of disorders which predominantly focus on the brain. This includes cancer, but also explains why some people have very large brains or suffer from epilepsy.

The genes
It took over two decades before the scientists were able to precisely determine which genes were of interest to them. Eventually, they narrowed it down to three genes, called AKT3, PIK3R2 and PIK3CA. These genes with impractical names all play a role in one specific signalling pathway. It is called the (P13K)/AKT pathway, and it helps cells turn on processes involved with metabolism, growth and proliferation. That also explains why it is involved with cancer, as uncontrolled activation of said pathway leads to uncontrolled growth, the hallmark of tumour development.
An overview of the AKT pathway. As visualized, it is incredibly complex. To sum it up: it starts with activation by cytokines, growth factors or other signalling molecules. Then, depending on what exactly needs to be done, several intracellular molecules are activated, which eventually leads to the effects mentioned above.
The effect
As said, these three genes all play a role in a single pathway. They were found to be involved with patients, especially children, with various brain malfunctions, which means mutations in the aforementioned genes can lead to disease. Specifically, PIK3CA was already known as a gene that can cause cancer when it is malfunctioning. However, the scientists found that the three genes do not work correctly in a wide variety of patients, including those suffering from epilepsy, autism, badly functioning blood vessels and malfunctions in skin growth. They were even implied in cases where patients were found to be suffering from an abnormally large brain, known as hydrocephalus. It is caused by an abnormal build-up of fluid in the brain, leading to increased pressure, which is quite dangerous.

The impact
Discovering how the (P13K)/AKT pathway relates to disease has established a novel therapeutic target for scientists. We now know that this is one to dive into, and discover how its signalling mechanism can lead to disease. In turn, this needs to provide us with new targets for drugs, that help us treat said diseases. Because the three genes are implied with several diseases, developing new treatments may be relevant for a wide variety of patients. The scientists think these findings will be especially relevant for children: because the discovered effects are of a genetic origin, they often manifest early in life.

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