Warner, Thomas Treharne; (1997) A molecular genetic study of inherited movements disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The introduction of recombinant DNA technology has led to the isolation of a number of neurological disease genes. This study describes the application of positional cloning techniques to three dominantly inherited movement disorders: Idiopathic Torsion Dystonia (ITD), Hereditary Essential Tremor (HET) and Dentatorubropallidoluysian atrophy DRPLA). A gene for ITD (DYT1) has been mapped to chromosome 9q34 in the United States. This study describes linkage analysis of 26 British families with ITD using markers from this region. Linkage was confirmed in a proportion of these kindreds. A multipoint linkage map was constructed which suggested that the DYT1 gene mapped to the interval between markers D9S63 and D9S64. Significant genetic heterogeneity was also demonstrated in this study, both for families with generalised ITD and also kindreds with focal ITD. For one large ITD kindred shown to be unlinked to markers on chromosome 9q34, a linkage study with one hundred microsatellite markers from throughout the genome was performed and a significant proportion of genome excluded from carrying the disease locus. An allelic association study confirmed the linkage disequilibrium between a particular haplotype of 9q34 markers in Ashkenazi Jewish families which had previously been reported in the United States. This points to a founder mutation occurring in this population before the migration of the Ashkenazim to Western Europe and the USA. A similar study, looking at index cases with non Jewish generalised ITD was unable to demonstrate any association. Analysis of a number of candidate genes mapping to chromosome 9q34 is described. A systematic linkage study on kindreds with HET is also described. 130 microsatellite markers were analysed in six HET pedigrees and lod scores presented. One potential area of linkage on chromosome 1q was studied with further markers and families, and a search for candidate genes mapping to this and other regions performed. DRPLA is a neurodegenerative disorder with characteristic pathology caused by an unstable trinucleotide repeat within the atrophin gene on chromosome 12p. This study describes the first identified European families with DRPLA. All kindreds with DPRLA have CAG expansions of 58 to 74 repeats, compared with 7 to 26 in control chromosomes. The size of the repeat was significantly inversely correlated with the age of onset. The role of unstable trinucleotide repeats in neurological disease is discussed in detail.

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