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ChAc is a rare progressive neurological disorder caused by mutations in a very complex gene. A better understanding of the biology underlying this disease helps develop better diagnostic tools, and opens up the possibility of discovering targets for possible future treatments.

Q: What diseases do you work on?

Antonio Velayos-Baeza: I work on neurological and neurodevelopmental diseases. I joined the group of Professor Anthony Monaco at the Welcome Trust Centre for Human Genetics: he was studying the genetics of these diseases. There are common but very complex disorders such as autism and dyslexia, and also monogenic rare disorders. My interest is mainly on the functional characterisation of genes and proteins that have been associated or found altered in these diseases.

To simplify things, I think it is better to focus on one of these diseases, a rare disorder called Chorea-acanthocytosis, called ChAc for short. This is a neurological disorder; it is recessive, which means that patients have mutations in both copies of the gene. It is an adult onset disease, meaning that the symptoms first appear between 20-40 years of age, in young adults. It is progressive and neurodegenerative; it involves movement disorder, epileptic seizures, tongue and lip biting. It is chronic, eventually leading to a short life expectancy.

Q: What is your approach to this disease?

AVB: Our approach is mainly from a molecular and cellular biology point of view. That means that we use DNA and RNA from patients, we work with proteins, cells and in vivo models. We try to answer a few questions, from very basic ones such as where the protein is in the cells, to more complicated ones, like which pathways are affected when this protein is altered.

Q: Can you give us an example of how your work has changed our understanding of this disease?

AVB: The pivotal finding from my work and previous work done by Professor Monaco's group is the identification of the gene that is altered in these patients. This is a very large gene known as VPS13A that produces a protein called chorein.

We have done extensive genetic studies in many patients and our goal is to identify mutations (changes in the DNA) that have an effect on the protein. We have learned that most of these mutations lead to the loss of the protein, so the protein is not present. We have also learned that there are a few mutations that instead of leading to the loss of the protein instead lead to a protein that is still there but does not work. This gives us a lot of information about the regions of the protein that are important for its function.

Q: What are the most important lines of research that have emerged in this field over the last 5-10 years?

AVB: For this protein disorder in particular, there has not been a lot of research into it, because it is a rare disorder. But I would like to take the opportunity to acknowledge the efforts of input by a small association of patient families that have actually provided great support to many researchers in the community. They have provided not only funding support, but they hvae also encouraged interaction between researchers. This group is the Advocacy for Neuroacanthocytosis Patients.

There have been many groups all around the world involved in looking at this disorder from different points of view. To single out one particular advance, for example, a connection has recently been made with autophagy: a cellular process involved in the degradation of toxic proteins or organelles. This seems to have a relevant connection with other neurological disorders.

Q: Why does this line of research matter and why should we fund it?

AVB: There has been a lot of effort put into the research of human disorders from a genetic point of view: finding the gene that is altered or associated with these disorders. The next logical step is to understand what these genes and proteins do, and which processes are affected. Studying these genes and proteins at the functional level is important for both basic biological knowledge of these disorders, but it also has a practical derivation: you may find specific targets where possible treatments can be developed.

Finally, this is a very rare disorder and there is usually not much effort put into rare disorders. They are often neglected and I think it is important to study these disorders because they can offer some valuable insights into other neurological disorders.

Q: How does your research fit into translational medicine within the department?

AVB: The long term goal is finding targets for possible treatments, but at the moment this is not an actual option for ChAc.

But another important issue for patients and their families is the proper diagnosis of the condition: sometimes a number of disorders have similar symptoms and the families or even the clinicians don't know exactly what they are. Knowing the gene now is very easy, they can understand finding the mutation in the gene. However, this particular gene is really complex, there are a lot of exomes and it involves large efforts just to sequence it, to find the mutations.

So a few years ago we developed a semi-diagnostic test that is based on the detection of the protein in blood samples. If we do not detect the protein, we say that this particular patient is affected. But the test is not 100% accurate: it gives false negatives - sometimes it detects the protein, but the tested case is actually a patient. In order to increase its accuracy, we are now working to develop and improve a version of this test.

Antonio Velayos-Baeza

Neurogenetics

Dr Antonio Velayos-Baeza is interested in two main projects: Chorea-acanthocytosis (ChAc), a rare autosomal-recessive disorder that is characterised by progressive neurodegeneration and red cell acanthocytosis (spiky red blood cells), and Developmental dyslexia, the most common of the childhood learning disorders.

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