Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa

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dc.contributor.advisorGreenberg, L J ; Bryer, Alan ; Wood, M ; Scholefield, Janineen_ZA
dc.contributor.authorBaine, Fiona Kebirungien_ZA
dc.date.accessioned2015-07-14T08:50:40Z
dc.date.available2015-07-14T08:50:40Z
dc.date.issued2010en_ZA
dc.descriptionIncludes bibliographical references (leaves 118-132).en_ZA
dc.description.abstractSpinocerebellar ataxia 1 (SCA1) is part of a broader group of dominant neurodegenerative disorders caused by an unstable CAG trinucleotide repeat. There is no known cure for this disease and symptoms worsen progressively culminating in death. The disease-causing mutation in SCA1 occurs in the ATXN1 gene. The function of the gene product (the ataxin-1 protein) is unknown, however; the protein has been linked to RNA processing in the cell. The first part of this study followed on a 1997 report of two founder haplotypes in the Mixed Ancestry SCA1 families in the Western Cape of South Africa, using microsatellites. The aim was to narrow the region investigated in the previous study, and confirm the existence of founder haplotypes using a SNP-based haplotype. The SNPbased haplotype was constructed using 4 SNPs in individuals from 5 different families of Mixed Ancestry origin from the Western Cape and the two founder events were confirmed. The SNP-based haplotype also shows the existence of a minimum common interval and indicates regions of possible break-points which may be useful in determining the extent and origins of the two haplotypes. The second aim of the study was to preferentially silence the mutant transcript of the ATXN1 gene by targeting a single nucleotide difference. Two of the SNPs genotyped for the SNP-based haplotype were found to be heterozygous in over half of the patient cohort. Eight shRNA effector molecules were screened against short target sequences incorporating one of these SNPs. Results are promising, with significant discrimination achieved between the wild-type and mutant alleles by targeting this SNP. This study has shown that RNAi may be developed as a beneficial therapeutic technique for a subset of SCA1 patients in South Africa.en_ZA
dc.identifier.apacitationBaine, F. K. (2010). <i>Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/13436en_ZA
dc.identifier.chicagocitationBaine, Fiona Kebirungi. <i>"Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2010. http://hdl.handle.net/11427/13436en_ZA
dc.identifier.citationBaine, F. 2010. Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Baine, Fiona Kebirungi AB - Spinocerebellar ataxia 1 (SCA1) is part of a broader group of dominant neurodegenerative disorders caused by an unstable CAG trinucleotide repeat. There is no known cure for this disease and symptoms worsen progressively culminating in death. The disease-causing mutation in SCA1 occurs in the ATXN1 gene. The function of the gene product (the ataxin-1 protein) is unknown, however; the protein has been linked to RNA processing in the cell. The first part of this study followed on a 1997 report of two founder haplotypes in the Mixed Ancestry SCA1 families in the Western Cape of South Africa, using microsatellites. The aim was to narrow the region investigated in the previous study, and confirm the existence of founder haplotypes using a SNP-based haplotype. The SNPbased haplotype was constructed using 4 SNPs in individuals from 5 different families of Mixed Ancestry origin from the Western Cape and the two founder events were confirmed. The SNP-based haplotype also shows the existence of a minimum common interval and indicates regions of possible break-points which may be useful in determining the extent and origins of the two haplotypes. The second aim of the study was to preferentially silence the mutant transcript of the ATXN1 gene by targeting a single nucleotide difference. Two of the SNPs genotyped for the SNP-based haplotype were found to be heterozygous in over half of the patient cohort. Eight shRNA effector molecules were screened against short target sequences incorporating one of these SNPs. Results are promising, with significant discrimination achieved between the wild-type and mutant alleles by targeting this SNP. This study has shown that RNAi may be developed as a beneficial therapeutic technique for a subset of SCA1 patients in South Africa. DA - 2010 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2010 T1 - Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa TI - Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa UR - http://hdl.handle.net/11427/13436 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/13436
dc.identifier.vancouvercitationBaine FK. Identification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africa. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2010 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/13436en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Human Geneticsen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherHuman Geneticsen_ZA
dc.titleIdentification of a suitable SNP for allele-specific silencing of the disease-causing gene in SCA1 patients in South Africaen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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