The search for tourette syndrome genes : a conceptual and experimental approach
| dc.contributor.advisor | Gericke, George S. | en_ZA |
| dc.contributor.advisor | Retief, Andries E. | en_ZA |
| dc.contributor.author | Simonic, Ingrid | en_ZA |
| dc.contributor.other | Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. | |
| dc.date.accessioned | 2012-08-27T11:34:32Z | |
| dc.date.available | 2012-08-27T11:34:32Z | |
| dc.date.issued | 1999-12 | |
| dc.description | Dissertation (PhD) -- University of Stellenbosch, 1999. | |
| dc.description.abstract | ENGLISH SUMMARY: Tourette syndrome has been reported in most populations throughout the world. Overall, there appears to be similar clinical phenomenology and psychopathology, which may serve as an indication of the biological nature for the condition. The diagnosis of Tourette syndrome represents a challenge for physicians because of clinical heterogeneity and often-present comorbidity with other known neurobehavioural conditions. Due to these clinical overlaps Tourette syndrome may serve as a model disorder for investigating the relationship between various neurological and behavioral domains of childhood reflecting either the expression of a common biological pathway or a common genetic background. The understanding of the genetic basis of Tourette syndrome is therefore of special importance, because it may provide useful insights for the study of other developmental disorders. However, the lack of objective biological markers of clinical manifestation together with a possible high phenocopy rate, unclear mode of inheritance, incomplete penetrance, and frequent bilinear transmission of predisposing genes represent major obstacles for those attempting to elucidate the genetic basis of Tourette syndrome. The research presented in this document is a result of six years' effort of the author and her collaborators to generate cytogenetic and molecular genetic data contributing to a better understanding of genetic and environmental factors affecting the phenotypic expression of Tourette syndrome. Theoretical and experimental results of this collaborative effort are assembled in seven articles (four published, three currently submitted for a publication) and a general introductory section relating to the problems, methods and methodology described and utilized in data collection for the individual papers. Taken as a whole, while the study of chromosome fragile site expression in Tourette syndrome probands yielded equivocal results leading to a number of rather speculative but interesting interpretations, the results of subsequent molecular genetic studies are far clearer. The three most valuable outcomes of these studies for future genetic investigations in Tourette syndrome gene-mapping efforts in the Afrikaner population, and complex genetic traits in general, are: I. The evidence for association/linkage of at least three genomic regions with Tourette syndrome in the Afrikaner population, with two of the regions (11q23 and 8q22) being suggestively linked to Tourette syndrome by others in different populations and employing different analytical methods. 2. The evidence for extended background linkage disequilibrium in the general Afrikaner population (> 5 cM) which further strengthens existing experimental data demonstrating the suitability of this population for gene-mapping efforts involving complex traits. 3. The proof based on real rather than computer-simulated data that sequential and semiparametric methods of analysis could be sufficiently powerful to generate cumulative evidence for positive linkage with the trait in the regions which repeatedly yielded both highly significant as well as suggestively significant disease-marker associations in the initial set of samples. | |
| dc.description.abstract | AFRIKAANSE OPSOMMING: Tourettesindroom is 'n algemene oorerflike neurobiologiese probleem wat in verskeie bevolkingsgroepe vanoor die wereld beskryf is. As gevolg van identiese fenomenologie en psigopatologie ten spyte van omgewingsverskille, is dit aanduidend van 'n sterk biologiese grondslag vir die toe stand. Die teenwoordigheid van kliniese meersoortigheid en die verhoogde voorkoms van 'n verskeidenheid komorbiede probleme by 'n subgroep van individue met Tourettesindroom, veroorsaak dikwels probleme met die akkurate identifisering hiervan. Dit skep egter ook geleenthede vir die bestudering by kinders, van verskeie neurologiese en gedragsmanifestasies gebaseer op 'n gemene genetiese substraat. Insig in die genetiese-omgewings wisselwerking by Tourettesindroom baan dus die weg vir begrip van ander ontwikkelingsprobleme wat ook by kinders aangetref word. Die afwesigheid van 'n betroubare biologiese merker of merkers vir hierdie kliniese entiteit, die algemene voorkoms van fenokopiee, komplekse oorerwingspatroon, onvolledige penetrasie en algemene verskynsel van oorerwing vanaf beide ouers, verteenwoordig 'n aantal formidabele struikelblokke ten opsigte van die analise van die genetiese basis van Tourettesindroom. TS word as een van die komplekse oorerflike toestande beskou, wat beteken dat daar duidelike oorerflike faktore by betrokke is, maar dat die oorerwing nie-mendelies van aard is. Die gebruiklike reduksionistiese benaderings wat so suksesvol was vir die analise van die enkelgeentoestande, werk nie meer onder hierdie omstandighedenie, en vir die rede word verskeie nie-parametriese of semiparametriese modelle ingespan. Die gedokumenteerde resultate verteenwoordig die navorsing uitgevoer tesame met plaaslike en oorsese medewerkers op hierdie gebied gedurende die laaste ses jaar. Die teoretiese en eksperimentele resultate word weergegee in sewe publikasies. Hiertydens is sitogenetiese en molekulere gegewens versamel in 'n poging om die genetiese en omgewingsfaktore onderliggend tot die ekspressie van Tourettesindroom te bepaal. Die teoretiese en eksperimentele resultate van hierdie poging word weergegee in sewe publikasies, waarvan vier reeds gepubliseer is, en 'n algemene inleidende afdeling wat die probleme en metodes bespreek soos tydens die versameling en analise van die data ervaar is. Die resultate word in twee afdelings aangebied: eerstens is daar die teoretisering ten opsigte van die bevinding van chromosomale breekbaarheid, wat aangedui is om verhoog te wees in die Tourette groep. Die betekenis van hierdie bevinding is tans nog onduidelik, en as gevolg van resolusieverskille nie direk met die DNA bevindings korreleerbaar nie. Hierdie merkerareas moet egter deurgaans in gedagte gehou word as moontlik aanwysend van die ligging van kandidaatgene vir Tourettesindroom. Die belangrikste gedeelte behandel egter die benadering tot die totale genoomsifiing, sowel as die veilgheidsmaatreels ingebou deur die heranalise van verskeie subgroepe en gevolglike replisering van resultate. Die mees waardevolle implikasies van hierdie navorsing ten opsigte van die uitstippeling van die pad vorentoe vir Tourettesindroom geenkartering by die Afrikaner, en komplekse oorerflike toestande in die algemeen, sluit die volgende in: 1. Die bewyse gevind vir die bevestiging van 3 genomiese streke soos oorspronklik deur die eerste fase assosiasiestudies aangetoon by die manifestering van Tourettesindroom in die Afrikaner, en waar ten minste twee van die gebiede (11q23 en 8q22) ook deur ander navorsers in ander bevolkingsgroepe met hierdie toestand gekoppel is; 2. Die kwantifisering van die stand van koppelings-disekwilibrium by 'n aantal lokusse in die Afrikaner genepoel van < 5cM. Hierdie gegewens versterk die gedagtes met betrekking tot die geskiktheid van hierdie bevolkingsgroep vir geenkarteringspogings vir komplekse toestande; 3. Die bewys, gebaseer op reele in stede van gemodelleerde data, dat opeenvolgende, semiparametriese analisemetodes oor voldoende statistiese krag beskik om kumulatiewe getuienis te verskaf vir positiewe koppeling van TS met streke wat ook in die oorspronkilke siektemerker assosiasiestudies betekenisvolle resultate gelewer het. | |
| dc.format.extent | 175 pages : ill. | |
| dc.identifier.uri | http://hdl.handle.net/10019.1/51511 | |
| dc.language.iso | en_ZA | en_ZA |
| dc.publisher | Stellenbosch : Stellenbosch University | |
| dc.rights.holder | Stellenbosch University | |
| dc.subject | Tourette syndrome -- Genetic aspects | en_ZA |
| dc.subject | Dissertations -- Genetics | en_ZA |
| dc.title | The search for tourette syndrome genes : a conceptual and experimental approach | en_ZA |
| dc.type | Thesis | en_ZA |
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