A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa

dc.contributor.advisorGreenberg, Jacquieen_ZA
dc.contributor.advisorHayden Michaelen_ZA
dc.contributor.authorBaine, Fiona Eugenie Kebirungien_ZA
dc.date.accessioned2016-07-08T10:42:06Z
dc.date.available2016-07-08T10:42:06Z
dc.date.issued2015en_ZA
dc.description.abstractHuntington disease (HD) is a devastating neurodegenerative condition characterised by a triad of symptoms: behavioural/psychiatric changes, cognitive decline and movement disorder. The dominantly inherited disease-causing mutation is an expanded trinucleotide (CAG) repeat in the Huntingtin(HTT) gene. Clinical symptoms are believed to be the result of degeneration of specific neuronal populations that are susceptible to the presence of a toxic expanded protein product. The disease is incurable and following the onset of symptoms, is progressively debilitating over 10-20 years and eventually fatal. Although typical epidemiological studies of prevalence are challenging for a genetic disorder such as HD, family studies and various other methods of ascertainment have been used to estimate its occurrence in different populations. Prevalence is therefore known to vary geographically; population-specific haplotypes have been hypothesised to be the basis of this variation between ethnic groups. High prevalence estimates for populations with European ancestry led to the supposition that the HD mutation was introduced to different regions by Europeans. In South Africa, a survey in the 1970s estimated that the prevalence of HD in the white and coloured subpopulations was similar at 2 per 100 000 individuals; while that in the black subpopulation was significantly lower, at less than 0.01 per 100 000 individuals. Molecular genetic analyses have since revealed links between the white and coloured subpopulations which would explain the similarity in prevalence; however, our knowledge of the genetics of HD in the black subpopulation, has been sorely lacking. This study provides, for the first time, a comprehensive analysis of the HTT gene in an African population. An evaluation of the normal distribution of CAG-tract sizes highlighted significant differences between the subpopulations. Haplotype analysis identified population-specific disease-associated haplotypes, confirming distinct origins of the HD mutation in the different subpopulations. In a coloured family with the rare juvenile form of the disease, DNA sequencing revealed no novel variants within the immediate vicinity of the CAG-tract that could be associated with the observed instability. This indicates that genome-wide analyses may be more useful in identifying factors related to repeat instability and future investigations are planned for a cohort of South African patients affected by juvenile onset HD.en_ZA
dc.identifier.apacitationBaine, F. E. K. (2015). <i>A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/20260en_ZA
dc.identifier.chicagocitationBaine, Fiona Eugenie Kebirungi. <i>"A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2015. http://hdl.handle.net/11427/20260en_ZA
dc.identifier.citationBaine, F. 2015. A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Baine, Fiona Eugenie Kebirungi AB - Huntington disease (HD) is a devastating neurodegenerative condition characterised by a triad of symptoms: behavioural/psychiatric changes, cognitive decline and movement disorder. The dominantly inherited disease-causing mutation is an expanded trinucleotide (CAG) repeat in the Huntingtin(HTT) gene. Clinical symptoms are believed to be the result of degeneration of specific neuronal populations that are susceptible to the presence of a toxic expanded protein product. The disease is incurable and following the onset of symptoms, is progressively debilitating over 10-20 years and eventually fatal. Although typical epidemiological studies of prevalence are challenging for a genetic disorder such as HD, family studies and various other methods of ascertainment have been used to estimate its occurrence in different populations. Prevalence is therefore known to vary geographically; population-specific haplotypes have been hypothesised to be the basis of this variation between ethnic groups. High prevalence estimates for populations with European ancestry led to the supposition that the HD mutation was introduced to different regions by Europeans. In South Africa, a survey in the 1970s estimated that the prevalence of HD in the white and coloured subpopulations was similar at 2 per 100 000 individuals; while that in the black subpopulation was significantly lower, at less than 0.01 per 100 000 individuals. Molecular genetic analyses have since revealed links between the white and coloured subpopulations which would explain the similarity in prevalence; however, our knowledge of the genetics of HD in the black subpopulation, has been sorely lacking. This study provides, for the first time, a comprehensive analysis of the HTT gene in an African population. An evaluation of the normal distribution of CAG-tract sizes highlighted significant differences between the subpopulations. Haplotype analysis identified population-specific disease-associated haplotypes, confirming distinct origins of the HD mutation in the different subpopulations. In a coloured family with the rare juvenile form of the disease, DNA sequencing revealed no novel variants within the immediate vicinity of the CAG-tract that could be associated with the observed instability. This indicates that genome-wide analyses may be more useful in identifying factors related to repeat instability and future investigations are planned for a cohort of South African patients affected by juvenile onset HD. DA - 2015 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa TI - A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa UR - http://hdl.handle.net/11427/20260 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/20260
dc.identifier.vancouvercitationBaine FEK. A molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africa. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2015 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/20260en_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.titleA molecular investigation of Huntington disease; origins of the mutation and current prevalence in South Africaen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
thesis_hsf_2015_baine_fiona_eugenie_kebirungi (1).pdf
Size:
3.04 MB
Format:
Adobe Portable Document Format
Description:
Collections