Analysis of genetic variants in the 5’ regulatory region of the ALAS1 gene in South African patients with Variegate Porphyria (VP)
Date
2007-03
Authors
Du Plessis, Nelita
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : University of Stellenbosch
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...
Description
Thesis (MSc (Genetics))—University of Stellenbosch, 2007.
Keywords
Porphyria -- South Africa -- Genetic aspects, Dissertations -- Genetics, Theses -- Genetics