The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders characterized by symptoms and signs of degeneration in the cerebellum, spinal cord and brainstem. To date, ten different loci causing autosomal dominant SCA have been mapped. In six types of SCA the disease is caused by the expansion of a trinucleotide CAG repeat which codes for a polyglutamine tract at the protein level. / The overall aim of this research project was to investigate various molecular genetic aspects of the autosomal dominant spinocerebellar ataxias: (1) to assess genetic heterogeneity with linkage studies in suitable families and to study the origin of the MJD/SCA3 mutation by linkage disequilibrium analysis; (2) to determine the relative frequency of the different types of SCA-(CAG)n mutations in a large group of patients from different ethnic origins; (3) to investigate molecular and clinico-pathological correlations in SCA patients in whom mutations were found and; (4) to investigate whether polyglutamine expansions are present in other forms of SCA using a monoclonal antibody. / Three large families segregating autosomal dominant SCA were tested for linkage to the SCA1, SCA2 and MJD/SCA3 loci by the maximum likelihood method. Two-point and multipoint linkage analysis showed that two families (SA and GK) were linked to the SCA2 locus. The third family (FC) was significantly excluded from the SCA1, SCA2 and SCA3/MJD loci. Additional markers were typed in the SCA2 candidate region in the two linked families. We were able to narrow down the SCA2 candidate region on ch12q and construct a fine genetic map of the region that provided important information for the positional cloning of the SCA2 gene. Linkage disequilibrium studies, using markers around the MJD/SCA3 gene found evidence of a founder effect in our MJD patients. However, distinct haplotypes were observed in patients originating from each of the two Azorean islands showing the highest disease prevalence; indicating that there are more than one founder mutation in the Azorean MJD population. / We studied a large group of unrelated SCA patients in order to determine the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37573 |
| Date | January 1999 |
| Creators | Lopes-Cendes, Iscia. |
| Contributors | Rouleau, Guy A. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001681221, proquestno: NQ55310, Theses scanned by UMI/ProQuest. |
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