Journal Article

Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer’s disease and variable expression

Jessie Theuns, Jurgen Del-Favero, Bart Dermaut, Cornelia M. van Duijn, Hubert Backhovens, Marleen Van den Broeck, Sally Serneels, Ellen Corsmit, Christine Van Broeckhoven and Marc Cruts

in Human Molecular Genetics

Volume 9, issue 3, pages 325-331
Published in print February 2000 | ISSN: 0964-6906
Published online February 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.3.325
Genetic variability in the regulatory region of  presenilin 1 associated with risk for Alzheimer’s disease and variable expression

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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.

Journal Article.  5455 words.  Illustrated.

Subjects: Genetics and Genomics

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