Abstract
BackgroundFriedreich ataxia (FRDA) is the most common form of hereditary ataxia characterized by the presence of a GAA trinucleotide repeat expansion within the first intron of the FXN gene. The expansion inhibits FXN gene expression resulting in an insufficiency of frataxin protein.Methodology/Principal FindingIn this study, computational analyses were performed on the 21.3 kb region upstream of exon 1 of the human FXN gene and orthologs from other species in order to identify conserved non-coding DNA sequences with potential regulatory functions. The conserved non-coding regions identified were individually analyzed in two complementing assay systems, a conventional luciferase reporter system and a novel Bacterial Artificial Chromosome (BAC)-based genomic reporter. The BAC system allows the evaluation of gene expression to be made in the context of its entire genomic locus and preserves the normal location and spacing of many regulatory elements which may be positioned over large distances from the initiation codon of the gene.Conclusions/SignificanceThe two approaches were used to identify a region of 17 bp located approximately 4.9 kb upstream of the first exon of the FXN gene that plays an important role in FXN gene expression. Modulation of FXN gene expression was found to be mediated by the action of the Oct-1 transcription factor at this site. A better understanding of cis-acting regulatory elements that control FXN gene expression has the potential to develop new strategies for the upregulation of the FXN gene as a therapy for FRDA.
Highlights
Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy
Identification of regions that may contain potential long-range, cis-acting regulatory elements controlling the expression of the human FXN gene was achieved by examining comparative genomic and regulatory data available on the UCSC Genome Browser [18,19] (Fig. 1A)
Regulatory data utilized consisted of regulatory potential (RP) scores computed from alignments of human, chimpanzee, macaque, mouse, rat, dog and cow [24,25]
Summary
Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy It is the most common form of hereditary ataxia with an estimated 2–3 affected individuals per 100,000 in European populations [1] and an estimated carrier frequency of 1 in 110 [2,3,4]. Homozygosity for a GAA trinucleotide repeat expansion within the first intron of the FXN gene is the most common cause of FRDA. The nontranslated GAA repeat expansion results in inhibition of gene expression and an insufficiency of frataxin. Friedreich ataxia (FRDA) is the most common form of hereditary ataxia characterized by the presence of a GAA trinucleotide repeat expansion within the first intron of the FXN gene. The expansion inhibits FXN gene expression resulting in an insufficiency of frataxin protein
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