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Molecular Insights into AADC Deficiency

Dr Riccardo Montioli

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Like all proteins, the AADC protein is made up of a chain of building blocks called amino acids. There are twenty different types of amino acid and these building blocks are joined together in a specific order to form a chain. The order of the amino acids in the chain is determined by the AADC gene that acts like a set of instructions for assembling the chain. AADC deficiency is caused by mutations in the AADC gene. These mutations lead to a change in one or more of the amino acids of the AADC protein. There are lots of different mutations in the AADC gene that can cause AADC deficiency. Each mutation may cause a different change in the amino acids that make up the AADC protein. This means that each different mutation will affect the AADC protein in a different way. It is this difference that may at least in part be responsible for the differences in severity and response to treatment between AADCd patients. We need to understand these differences in detail to be able to design better treatment regimes and hopefully discover new ways to treat AADC deficiency.

Professor Carla Voltattorni and Dr Riccardo Montioli have been undertaking a detailed investigation of how individual mutations that cause AADC deficiency affect the AADC protein. They now aim to extend their research to investigate even more mutations that cause AADC deficiency. To achieve this they will artificially produce AADC proteins from AADC genes that contain different mutations that cause AADC deficiency. This will be done by using a technique known as “recombinant protein expression”. These proteins will then be highly purified to allow accurate analysis and will be subjected to a barrage of complex biochemical and biophysical tests.

The tests are designed to examine the different ways that the AADC protein can be affected, including:

  • how well the protein binds to the substrate L-dopa

  • the characteristics of the metabolism that produces dopamine

  • how well the protein binds to the cofactor pyridoxal 5’-phosphate

  • changes in the stability of the protein

  • changes in the folding and 3D structure of the protein

The Voltattorni Laboratory has already identified mutations that affect the folding and 3D structure of the AADC protein. Proteins that do not fold correctly can cause problems for cells and there are multiple mechanisms for dealing with these proteins. Often cells will simply degrade proteins that are not folded correctly and so this could decrease the availability of AADC protein. Alternatively, cells can have stronger reactions to misfolded proteins and this could have wider effects on the cells ability to function. The laboratory now aims to examine how these AADC proteins function inside cells, whether the proteins are degraded and how the cells cope with these proteins. They will also attempt to rescue the misfolded AADC proteins by using different forms of vitamin B6. It is hoped that this may help the proteins to fold correctly and this could lead to improvements in vitamin B6 therapy for AADC deficiency.

We all have two copies of the AADC gene and patients with AADC deficiency have one mutation in each copy of their AADC gene. Those two mutations can be exactly the same or they can be different. Patients with two different mutations are known as “heterozygotes”. These patients will produce two different chains of amino acids and the Voltattorni lab is also aiming to investigate how this will affect the function and structure of the AADC protein.

The AADC Research Trust has awarded 20,000 EUR, from September 2015, for a one-year postdoctoral fellowship for Dr Riccardo Montioli to conduct this project in the laboratory of Prof. Voltattorni at the Department of Life Sciences and Reproduction, University of Verona, Italy.

Previous publications examining the molecular details of AADC deficiency from Dr Montioli and Prof. Voltattorni:

Montioli, R., Cellini, B., & Borri Voltattorni, C. (2011). Molecular insights into the pathogenicity of variants associated with the aromatic amino acid decarboxylase deficiency. Journal of Inherited Metabolic Disease, 34(6), 1213–24.

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Montioli, R., Oppici, E., Cellini, B., Roncador, A., Dindo, M., & Voltattorni, C. B. (2013). S250F variant associated with aromatic amino acid decarboxylase deficiency: molecular defects and intracellular rescue by pyridoxine. Human Molecular Genetics, 22(8), 1615–24.

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Montioli, R., Dindo, M., Giorgetti, A., Piccoli, S., Cellini, B., & Voltattorni, C. B. (2014). A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications. Human Molecular Genetics, 23(20), 5429–40.

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What the Founder & Managing Director, Lisa Flint, says about this project ... INSIGHTS

From the first time we met Dr Riccardo Montioli at our 2011 International AADCd Conference, we knew he had an extraordinary interest in our disease.  We are truly grateful to him for the years he has already dedicated to researching the genetic variations of AADC deficiency and we are very pleased we were able to financially support this project.

Trying to enhance our understanding of the genetic variations within this disease is vitally important to recognising the extreme differences we see in its clinical presentation.  Once these are better explained we can intricately describe the disease and thus identify and diagnose patients across all spectrums of severity, from mild to severe. Genetic understanding will also help us tailor treatment strategies’ which will potentially benefit our children directly and allow us to make informed decisions about their overall care.  This research is also an important adjunct to our iPSC project and the impending AADC Gene Therapy trial.

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