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. 2006 Jun;78(6):936-46.
doi: 10.1086/504044. Epub 2006 Apr 10.

Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease

Jessie Theuns  1 , Nathalie Brouwers, Sebastiaan Engelborghs, Kristel Sleegers, Veerle Bogaerts, Ellen Corsmit, Tim De Pooter, Cornelia M van Duijn, Peter P De Deyn, Christine Van Broeckhoven
Affiliations

Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease

Jessie Theuns et al. Am J Hum Genet. 2006 Jun.

Abstract

Genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases. Also, expression levels of APP are essentially regulated by its core promoter and 5' upstream regulatory region and correlate with amyloid beta levels in Alzheimer disease (AD) brains. Here, we systematically sequenced the proximal promoter (-766/+204) and two functional distal regions (-2634/-2159 and -2096/-1563) of APP in two independent AD series with onset ages < or =70 years (Belgian sample, n=180; Dutch sample, n=111) and identified eight novel sequence variants. Three mutations (-118C-->A, -369C-->G, and -534G-->A) identified only in patients with AD showed, in vitro, a nearly twofold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome. These mutations either abolished (AP-2 and HES-1) or created (Oct1) transcription-factor binding sites involved in the development and differentiation of neuronal systems. Also, two of these clustered in the 200-bp region (-540/-340) of the APP promoter that showed the highest degree of species conservation. The present study provides evidence that APP-promoter mutations that significantly increase APP expression levels are associated with AD.

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Figures

Figure 1
Figure 1
Conservation plot of the APP 5′ upstream region. Plots were generated using the VISTA software, and tracks were presented on the UCSC Genome Bioinformatics Browser. Conserved regions are defined as regions with a conservation score ⩾50% that are ⩾20 bp. Horizontal black lines crossing the conservation plots mark the 70% conservation boundary. Regions of high conservation are colored as exons (dark blue), UTRs (light blue), or noncoding sequences (pink).
Figure 2
Figure 2
Transcriptional activity of APP promoter variants. A, Bars represent firefly/Renilla luciferase ratios for the different constructs (RLA). Values are mean (±SEM) of at least eight independent measurements. The significance of differences in expression was calculated using the Mann-Whitney U test. P values are presented above the bars. B, Relative increase of APP promoter activity compared with WT.
Figure 3
Figure 3
Allele-specific binding of transcription factors. EMSA analysis of allele-specific effect of −118C→A (A), −369C→G (B), and −534G→A (C) on the interaction of nuclear protein complexes extracted from SH-SY5Y cells. DIG-labeled double-stranded probes (200 fmol) were incubated with 10 μg nuclear extract from SH-SY5Y cells. In competition experiments, 50-fold excess of unlabeled probe was added before the addition of the labeled probes.
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References

Web Resources

    1. Alzheimer Disease & Frontotemporal Dementia Mutation Database, http://www.molgen.ua.ac.be/ADMutations/
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for APP [accession number D87675.1])
    1. Genetic Service Facility, http://www.vibgeneticservicefacility.be/
    1. International HapMap Project, http://www.hapmap.org/
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AD, APP, PSEN1, PSEN2, MAPT, PRNP, PD, NR4A2, SNCA, and PARK2)

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