| abstract |  Despite the fact that 11 SCA genes have already been identified, 30% of the ADCA families still remain undiagnosed. These so-called “SCA-negative” Dutch families are the basis of this research. The aim of this project was to collect genetic material from these Dutch families and to localize and identify novel SCA genes that cause ADCA. Linkage analysis was used to localize the disease-genes in two large Dutch ADCA families, in whom no mutations had been identified in the known SCA genes. After exclusion of the already identified SCA loci with two-point lod scores < -2, we performed genomewide screens and identified two additional SCA loci in the Dutch ADCA population, SCA19 (Chapter 2) and SCA23 (Chapter 3), respectively. However, the majority of the SCA-negative families are too small for traditional linkage analysis and an alternative approach was used to localize the disease genes in these families. This approach is based on the existence of founder mutations in the ADCA population, as illustrated for SCA3 and SCA6 (Chapter 4) and SCA14 (Chapter 6). These results implied that independently referred ADCA families could actually be linked into larger families. To make use of this phenomenon, we set out to use a shared haplotype analysis (SHA) to localize and identify SCA genes from the known SCA loci, as shown for the SCA14 locus (Chapter 5). In addition, we studied the implications of two SCA14 mutations on the cellular localization, translocation behavior, and activity of protein kinase C gamma in COS-7 cells. These results are described in Chapter 7. Finally, the implications of the results from these studies are discussed in Chapter 8. |
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