Project details

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Unraveling the genetic and biological pathways of spinocerebellar ataxia

Keywords:
neurodegeneration exome sequencing human genetics

Researchers:
Dr. D.S. Verbeek

Nature of the research:
This project involves human genetics using the latest sequence technologies and in vitro and/or in vivo work, in order to identify novel SCA genes and to unravel the disease pathology.

Fields of study:
cell biology molecular biology genetics

Background / introduction
The Spinocerebellar ataxias (SCAs) are a class of genetically heterogeneous disorders of which 36 different SCA subtypes are already known and in which the disease gene has been identified in 20 types. These neurodegenerative disorders are all characterized by selective loss of neuronal cells in the cerebellum leading to cerebellar ataxia.
Despite the fact that 17 SCA genes have been identified, in 30% of the ataxia patients we can still not make a genetic diagnosis because no mutations can be found in the known SCA genes. This suggests that only two-thirds of the SCA genes have been identified. Interestingly, different mutations in the 20 SCA genes lead to comparable clinical manifestations although they are seemingly functionally unrelated. This suggests overlap in a limited number of affected pathways.
Research question / problem definition
This project aims to:
i. To identify novel genes that play a role in cerebellar neurodegeneration and to classify the remaining one-third of ataxia patients who are genetically undiagnosed.
ii. To characterize the corresponding pathways and identify the underlying disease mechanism.
Workplan
We will use exome sequencing to identify novel SCA genes in (a) families in which the disease genes have already been mapped by linkage- or shared haplotype analysis and (b) families in which we have no prior knowledge about the disease gene location. In addition, potentially disease-causing variations will be functionally screened in cell- and Drosophila models. Our project will identify novel SCA genes and the cellular processes that contribute to cerebellar neurodegeneration and will improve current genetic diagnostics.
With an internship you can participate in the various parts of the project. The final working program will be made in discussion with the student, depending on research interest.
References
1. Durr, A. (2010). Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol 9, 885-894.
2. Bakalkin, G., Watanabe, H., Jezierska, J., Depoorter, C., Verschuuren-Bemelmans, C., Bazov, I., Artemenko, K.A., Yakovleva, T., Dooijes, D., Van de Warrenburg, B.P., et al. (2010). Prodynorphin Mutations Cause the Neurodegenerative Disorder Spinocerebellar Ataxia Type 23. Am J Hum Genet. Nov 12;87(5):736.
3. Wang, J.L., Yang, X., Xia, K., Hu, Z.M., Weng, L., Jin, X., Jiang, H., Zhang, P., Shen, L., Guo, J.F., et al. (2010). TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 133, 3510-3518.
4. Duenas, A.M., Goold, R. & Giunti, P. (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129, 1357-70.
5. Verbeek, D.S. Spinocerebellar ataxia type 23: a genetic update. Cerebellum 8, 104-7 (2009).
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