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The genetics of Gilles de la Tourette syndrome:- A linkage study

Brett, Peter Mark; (1996) The genetics of Gilles de la Tourette syndrome:- A linkage study. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Gilles de la Tourette Syndrome (GTS) is a neuropsychiatric disorder defined by the presence of multiple motor and one or more vocal tics and by the observation of a spectrum of symptoms which include involuntary thoughts, compulsive behaviours or movements including chronic motor tics (CMT). GTS and CMT are thought to share the same genetic aetiology when found within the same family. Segregation analyses of family data have shown an autosomal dominant mode of transmission with variable penetrance. Since it is likely that single major loci contribute to the genetic susceptibility to GTS/CMT it was hypothesised that linkage analysis with genetic markers could localise a mutation to a specific chromosome. In order to test this hypothesis three approaches were adopted. The first approach was to try and detect non random segregation between marker alleles and disease locus using the lod method, in total over 70 polymorphic markers including blood groups, RFLPs, VNTRs, minisatellite and microsatellite polymorphisms were genotyped. In the second approach it was hypothesised that a case of GTS in a patient carrying a chromosome 3 to 8 translocation was caused by the cytogenetic abnormality and that clues to the general aetiology of GTS/CMT might be derived from the specific chromosomal loci disrupted by the translocation. The third approach involved testing the role of known genes expressed in the CNS for their potential role in the aetiology of GTS. All three of these approaches demanded extensive linkage analysis and required the incorporation of variable disease models. Furthermore adjustment of penetrance parameters needed to be made in order to take into account the possible presence of non genetic cases or phenocopies and incomplete penetrance within the families studied. Two lod scores above 2.00 were found. One resulted from testing the hypothesis that random markers might show linkage to the disease and was found on chromosome one. The other positive lod score above 2.00 resulted from the hypothesis that the 3 to 8 translocation was involved in GTS and was found using markers localised to the region implicated on chromosome 3. Linkage analysis was primarily carried out on a single large kindred, but where positive lod scores were found the sample was enlarged, and additional markers were used. When the hypothesis of chromosome 3 involvement was tested further in the enlarged sample a positive lod score of 2.98 was found on chromosome 3. A cell hybrid was produced from the GTS patient with the translocation in order to facilitate accurate mapping of linkage markers relative to the chromosome 3 and 8 breakpoints. It was found that the breakpoint on chromosome 3 was proximal to the marker loci used to obtain the positive lod score. Further work, including the use of chromosome-walking to obtain novel polymorphic microsatellite CA repeat sequences in the area, and repeated multipoint linkage analyses eventually excluded the whole region on chromosome 3 near the cytogenetic abnormality as well as the break-point on chromosome 8. The third approach of investigating candidate genes focused on neuro-receptors and neurotransmitter enzymes. The dopamine Dl, D2, D3, D4 and D5 receptors and the dopamine pathway enzymes, dopamine-beta-hydroxylase and tyrosine hydroxylase, have all been hypothesised to be involved in susceptibility to GTS/CMT. All such candidate genes tested were excluded in two point and multipoint tests of linkage. In order to test the hypothesis that glutamate neurotransmitter receptor genes, such as the NMDARl receptor could be involved in the genetic aetiology of GTS further laboratory work needed to be carried out. A cDNA clone of GRINl (NMDA 1 subunit), a newly cloned neuroreceptor, was used to screen genomic libraries to find an associated RFLP or microsatellite marker for linkage analysis. A variable number tandem repeat (VNTR) was isolated and mapped by FISH and linkage analysis to chromosome 9q34.3. The research failed to confirm linkage at the favoured loci on chromosomes 3 and 8 and did not support linkage at other loci. Work in other laboratories has also failed so far to implicate a major locus component in the genetic liability to Tourette Syndrome. The most likely explanation is that there is locus heterogeneity in GTS with several single major loci causing genetic susceptibility within any given family.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The genetics of Gilles de la Tourette syndrome:- A linkage study
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10103295
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