Journal Article

Alzheimer-associated C allele of the promoter polymorphism −22C>T causes a critical neuron-specific decrease of presenilin 1 expression

Jessie Theuns, Jacques Remacle, Richard Killick, Ellen Corsmit, Krist'l Vennekens, Danny Huylebroeck, Marc Cruts and Christine Van Broeckhoven

in Human Molecular Genetics

Volume 12, issue 8, pages 869-877
Published in print April 2003 | ISSN: 0964-6906
Published online April 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg098
Alzheimer-associated C allele of the promoter polymorphism −22C>T causes a critical neuron-specific decrease of presenilin 1 expression

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We, amongst others, have shown that CC homozygosity at the −22C>T promoter polymorphism in presenilin 1 (PSEN1) is associated with increased risk for Alzheimer's disease (AD). Also, studies in AD brains suggested that CC homozygosity increased the risk for AD by increasing the Aβ load. We characterized the PSEN1 promoter by deletion mapping, and analysed the effect of the −22C and −22T alleles on the transcriptional activity of PSEN1 in a transient transfection system. We showed a neuron-specific 2-fold decrease in promoter activity for the −22C risk allele, which in homozygous individuals would lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13 bp region (−33/−20) spanning the −22C>T polymorphism harbours a binding site for a negative regulatory factor. This factor has a higher affinity for the −22C risk allele and is strongly dependent on downstream sequences for cell-type-specific expression differences. Together, these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons.

Journal Article.  5943 words.  Illustrated.

Subjects: Genetics and Genomics

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