Analysis of genetic variants in the 5’ regulatory region of the ALAS1 gene in South African patients with Variegate Porphyria (VP)

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dc.contributor.advisor Warnich, L.
dc.contributor.advisor Zaahl, M. G.
dc.contributor.author Du Plessis, Nelita en_ZA
dc.contributor.other University of Stellenbosch. Faculty of Agrisciences. Dept. of Genetics.
dc.date.accessioned 2007-11-29T12:34:45Z en_ZA
dc.date.accessioned 2010-06-01T08:53:56Z
dc.date.available 2007-11-29T12:34:45Z en_ZA
dc.date.available 2010-06-01T08:53:56Z
dc.date.issued 2007-03 en_ZA
dc.identifier.uri http://hdl.handle.net/10019.1/2625
dc.description Thesis (MSc (Genetics))—University of Stellenbosch, 2007.
dc.description.abstract The porphyrias are a group of genetic disorders arising from mutations in either one of the final seven genes encoding the haeme synthesis enzymes. These disease-causing mutations lead to an enzyme deficiency that disrupts normal haeme production, resulting in clinical features due to the subsequent accumulation of porphyrin precursors. Like most of the porphyrias, variegate porphyria (VP) is characterized by high inter- and intra- familial clinical variability, with no apparent genotype-phenotype correlation. The delta-aminolevulinate synthase-1 gene (ALAS1) is an apparent candidate gene to explain the variable clinical expression observed in VP, since it encodes the first and rate-determining enzyme of haeme synthesis. Several studies have defined important regulatory elements for the human-, rat- and chicken ALAS1 gene that regulate expression patterns of this gene. It was hypothesized that in VP individuals, variants within/near critical regulatory sites might alter the transcription rate of this gene, and consequently increase/decrease the amount of haeme precursors accumulating as a result of the defective haeme synthesis enzyme. The aim of this study was to identify genetic variants that could influence gene expression in the proximal promoter area of the ALAS1 gene, as well as the two ALAS1-drug responsive enhancer sequences (ADRES) located further upstream. DNA (2133 bp per patient) of 19 clinically defined VP patients was analysed by polymerase chain reaction (PCR) and semiautomated DNA sequencing. Subsequently, in silico analyses using appropriate software programs, and in vitro studies using the luciferase reporter system, were performed to investigate the functionality of the identified variants on ALAS1 gene transcription... en_ZA
dc.format.extent 2698307 bytes en_ZA
dc.format.mimetype application/pdf en_ZA
dc.language.iso en
dc.publisher Stellenbosch : University of Stellenbosch
dc.subject Porphyria -- South Africa -- Genetic aspects en
dc.subject Dissertations -- Genetics en
dc.subject Theses -- Genetics en
dc.title Analysis of genetic variants in the 5’ regulatory region of the ALAS1 gene in South African patients with Variegate Porphyria (VP) en_ZA
dc.type Thesis en_ZA
dc.rights.holder University of Stellenbosch


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