title: Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression.
abstract: Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.
authors.affiliation: Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Department of Biochemistry, Antwerpen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Theuns
authors.forename: J
authors.initials: J
authors.lastname: Del-Favero
authors.forename: B
authors.initials: B
authors.lastname: Dermaut
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: H
authors.initials: H
authors.lastname: Backhovens
authors.forename: M V
authors.initials: MV
authors.lastname: Van den Broeck
authors.forename: S
authors.initials: S
authors.lastname: Serneels
authors.forename: E
authors.initials: E
authors.lastname: Corsmit
authors.forename: C V
authors.initials: CV
authors.lastname: Van Broeckhoven
authors.forename: M
authors.initials: M
authors.lastname: Cruts
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D053764:Presenilin-1; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D012307:Risk Factors; D014162:Transfection
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D004247:DNA