Dineke Verbeek
Throughout the last years, partner Dineke Verbeek has been at the forefront of the identification and characterization of SCA genes. To achieve success in the form of the disease gene identification for SCA23 and SCA19, she has been using the latest genotyping and sequencing technologies, including the next generation technology, exome sequencing (Bakalkin et al., AJHG 2010 and Duarri et al., Annals of Neur 2012).
In addition, she recently initiated, in collaboration with the EuroSCA consortium, a pilot study to identify modifiers for the age of onset variation observed in SCA3. Here, eQTL-SNPs mapped to the genes MOAG4 and HSPB6, both in vitro very strong modifiers of polyQ-protein aggregation (van Ham et al., Cell, 2010 and Hageman et al., Mol. Cell, 2010), are tested for association with age of onset variation in SCA3 (work in progress). The identification of potential modifiers for SCA3 disease in human will be crucial towards developing a treatment for this disease.
Disease gene identification strategy Unique collections of patients with genetically unexplained neurodegenerative disorders are subjected to genome-wide genotyping followed by shared haplotype analysis in combination with exome sequencing. All in silico predicted pathogenic variants, that are absent in all control databases and 500 Dutch exomes (goNL project) are validated by Sanger sequencing and checked for co-segregation. Remaining variants are further analyzed using a home-made gene-gene interaction network based on co-expression of known disease genes. The most potential disease gene candidates are functionally validated in cell - and Drosophila models
References:
Bakalkin G, Watanabe H, Jezierska J, Depoorter C, Verschuuren-Bemelmans C, Bazov I, Artemenko KA, Yakovleva T, Dooijes D, Van de Warrenburg BP, Zubarev RA, Kremer B, Knapp PE, Hauser KF, Wijmenga C, Nyberg F, Sinke RJ, Verbeek DS. "Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.", American Journal of Human Genetics (2010) Nov 12;87(5):593-603.
Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Küsters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS. "Mutations in potassium channel kcn3 cause spinocerebellar ataxia type 19", Ann Neurol. 2012 Dec;72(6):870-80. doi: 10.1002/ana.23700.