title: A polymorphic microsatellite repeat within the ECE-1c promoter is involved in transcriptional start site determination, human evolution, and Alzheimer's disease.
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 β 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.
authors.affiliation: Center for Cardiovascular Research/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.
authors.forename: Yaosi
authors.initials: Y
authors.lastname: Li
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.forename: Peter
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authors.lastname: Marschall
authors.forename: Michael
authors.initials: M
authors.lastname: Klein
authors.forename: Antonia
authors.initials: A
authors.lastname: Hope
authors.forename: Jens
authors.initials: J
authors.lastname: Schacherl
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schmitz
authors.forename: Mario
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authors.lastname: Menk
authors.forename: Jan H
authors.initials: JH
authors.lastname: Schefe
authors.forename: Jana
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authors.lastname: Reinemund
authors.forename: Rebecca
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authors.lastname: Hugel
authors.forename: Peter
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authors.lastname: Walden
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlosser
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.forename: Julia
authors.initials: J
authors.lastname: Schimkus
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.forename: Lutz
authors.initials: L
authors.lastname: Frölich
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klare
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kirsch
authors.forename: Kristin
authors.initials: K
authors.lastname: Schmerbach
authors.forename: Sylvia
authors.initials: S
authors.lastname: Scheele
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grittner
authors.forename: Frank
authors.initials: F
authors.lastname: Zollmann
authors.forename: Petra
authors.initials: P
authors.lastname: Goldin-Lang
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D005075:Biological Evolution; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000235:genetics / Q000503:physiopathology; D002850:Chromatography, Gel; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D024202:Electrophoretic Mobility Shift Assay; D000072396:Endothelin-Converting Enzymes; D005838:Genotype; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics*; D023282:Nuclease Protection Assays; D002679:Pan troglodytes; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D012313:RNA; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes