Identification of a novel functional deletion variant in the 5'-UTR of the DJ-1 gene

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dc.contributor.authorKeyser, Rowena J.en_ZA
dc.contributor.authorVan der Merwe, Lizeen_ZA
dc.contributor.authorVenter, Mauritzen_ZA
dc.contributor.authorKinnear, Craigen_ZA
dc.contributor.authorWarnich, Louiseen_ZA
dc.contributor.authorCarr, Jonathanen_ZA
dc.contributor.authorBardien, Sorayaen_ZA
dc.date.accessioned2013-05-02T07:29:43Z
dc.date.available2013-05-02T07:29:43Z
dc.date.issued2009-10
dc.descriptionPublication of this article was funded by the Stellenbosch University Open Access Fund.en_ZA
dc.descriptionThe original publication is available at http://www.biomedcentral.com/bmcmedgenet/en_ZA
dc.descriptionBibliography.
dc.description.abstractBackground: DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD). Various mutations in the DJ-1 (PARK7) gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in DJ-1 and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient. Methods: The possible effect of the deletion on promoter activity was investigated using a Dual- Luciferase Reporter assay. The DJ-1 5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2)-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (in silico) cis-regulatory analysis of DJ-1 promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH™ and rVISTA platforms. Results: A novel 16 bp deletion variant (g.-6_+10del) was identified in DJ-1 which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2)-M17 cells compared to the wild-type (P < 0.0001), indicating the importance of the 16 bp sequence in transcription regulation. The activity of both constructs was up-regulated during oxidative stress. Bioinformatic analysis revealed putative binding sites for three transcription factors AhR, ARNT, HIF-1 within the 16 bp sequence. The frequency of the g.-6_+10del variant was determined to be 0.7% in South African PD patients (2 heterozygotes in 148 individuals). Conclusion: This is the first report of a functional DJ-1 promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the DJ-1 promoter and whether this variant confers a risk for PD.en_ZA
dc.description.sponsorshipStellenbosch University Open Access Funden_ZA
dc.description.versionPublishers' versionen_ZA
dc.format.extent10 p. : ill.
dc.identifier.citationKeyser, R. J. et al. 2009. Identification of a novel functional deletion variant in the 5'-UTR of the DJ-1 gene. BMC Medical Genetics, 10:105, doi:10.1186/1471-2350-10-105.en_ZA
dc.identifier.issn1471-2350 (print)
dc.identifier.issn1471-2350 (online)
dc.identifier.otherdoi:10.1186/1471-2350-10-105
dc.identifier.urihttp://hdl.handle.net/10019.1/80713
dc.language.isoen_ZAen_ZA
dc.publisherBioMed Centralen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectNervous system -- Degenerationen_ZA
dc.subjectAlzheimer's diseaseen_ZA
dc.subjectParkinson's diseaseen_ZA
dc.subjectOxidative stressen_ZA
dc.subjectOxidative stress and neurodegenerative diseasesen_ZA
dc.titleIdentification of a novel functional deletion variant in the 5'-UTR of the DJ-1 geneen_ZA
dc.typeArticleen_ZA
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