A Polymorphic Microsatellite Repeat within the ECE-1c Promoter Is Involved in Transcriptional Start Site Determination, Human Evolution, and Alzheimer's Disease

Yaosi Li, Kerstin Seidel, Peter Marschall, Michael Klein, Antonia Hope, Jens Schacherl, Jennifer Schmitz, Mario Menk, Jan H. Schefe, Jana Reinemund, Rebecca Hugel, Peter Walden, Andreas Schlosser, Rudolf Volkmer, Julia Schimkus, Heike Koelsch, Wolfgang Maier, Johannes Kornhuber, Lutz Froelich, Sabrina KlareSebastian Kirsch, Kristin Schmerbach, Sylvia Scheele, Ulrike Grittner, Frank S. Zollmann, Petra Goldin-Lang, Oliver Peters, Ulrich Kintscher, Thomas Unger, Heiko Funke-Kaiser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 ? 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.
Original languageEnglish
Pages (from-to)16807-16820
JournalJournal of Neuroscience
Issue number47
Publication statusPublished - 21 Nov 2012

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