A polymorphic microsatellite repeat within the ECE-1c promoter is involved in transcriptional start site determination, human evolution, and Alzheimer's disease

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Item Type:	Article
Title:	A polymorphic microsatellite repeat within the ECE-1c promoter is involved in transcriptional start site determination, human evolution, and Alzheimer's disease
Creators Name:	Li, Y., Seidel, K., Marschall, P., Klein, M., Hope, A., Schacherl, J., Schmitz, J., Menk, M., Schefe, J.H., Reinemund, J., Hugel, R., Walden, P., Schlosser, A., Volkmer, R., Schimkus, J., Koelsch, H., Maier, W., Kornhuber, J., Froelich, L., Klare, S., Kirsch, S., Schmerbach, K., Scheele, S., Grittner, U., Zollmann, F., Goldin-Lang, P., Peters, O., Kintscher, U., Unger, T. and Funke-Kaiser, H.
Abstract:	Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid {beta} content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG](m)-[CA](n) ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.
Keywords:	Alzheimer Disease, Aspartic Acid Endopeptidases, Biological Evolution, Cardiovascular Diseases, DNA, Electrophoretic Mobility Shift Assay, Gel Chromatography, Genetic Promoter Regions, Genetic Transcription, Genotype, Metalloendopeptidases, Microsatellite Repeats, Nuclease Protection Assays, Pan troglodytes, Poly(ADP-ribose) Polymerases, Real-Time Polymerase Chain Reaction, RNA, Western Blotting, Animals
Source:	Journal of Neuroscience
ISSN:	0270-6474
Publisher:	Society for Neuroscience
Volume:	32
Number:	47
Page Range:	16807-16820
Date:	21 November 2012
Official Publication:	https://doi.org/10.1523/JNEUROSCI.2636-12.2012
PubMed:	View item in PubMed

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