Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD

Abstract

We have analyzed the 5Ј-upstream promoter region of the presenilin 2 gene (PSEN2) for regulatory elements and examined Alzheimer disease (AD) patients and non-demented individuals for polymorphisms in the 5Ј upstream promoter region of the PSEN2 gene. Direct sequencing analysis detected a common single adenine (A) nucleotide deletion polymorphism in the upstream promoter region of the PSEN2 gene. Examination of cohorts of AD patients and agematched control individuals revealed no statistically significant differences in the frequency of this polymorphism when compared with the total sample of AD patients and control individuals. However, subgroup and regression analysis suggested that the relatively rare −A/−A genotype increases risk of AD among subjects lacking apolipoprotein E (APOE) ⑀4 and among persons ages 65 years and younger. DNA sequence and DNA-protein binding analysis demonstrated that this mutation negates binding with putative repressor transcription factor (TF), interferon regulatory factor 2 (IRF2), in nuclear extracts prepared from the aged human brain neocortex. However this mutation creates a potential regulatory element, C/EBPbeta, that is responsive to pro-inflammatory (PI) induction. The expression activity assay with luciferase reporter gene into normal human neural progenitor cells in primary culture shows that the mutant PSEN2 regulatory region exhibits a 1.8-fold higher level of basal expression and is sensitive to IL−1␤ and A␤42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL−1␤+A␤42]. These results suggest that under Pl and oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that consequently these may play a role in the induction and/or proliferation of a Pl response in AD brain.

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

“…This strategy results from two major observations: (i) the expression of numerous genes is modified during AD aetiology, [4][5][6][7][8] (ii) polymorphisms within promoters of the APOE, PS1, PS2 and APP genes have been associated with the occurrence of AD. [9][10][11][12] Consequently, we assumed that genes located in one of the loci of interest defined by previous genome scans and exhibiting a differential expression between patients and controls, could constitute potential candidate genes for AD. We applied our strategy to nine different chromosomal regions previously identified by genome scan studies 13 and selected a candidate gene expressed in cases but not in controls, the ornithine transcarbamylase (OTC) located on Xp21.1.…”

Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

“…For example, an insertion/deletion polymorphism (A,ÀA) in the upstream promoter region of the PSEN2 (presenilin 2) gene, when homozygous (ÀA/ÀA), has been suggested to increase the risk for Alzheimer disease; DNA-protein binding analysis experiments suggested that this site interacts with a TF. 26 An SNP in the human SCGB3A2 (secretoglobin, family 3A, member 2) promoter that regulates transcription was reported associated with asthma, 27 and an SNP in the promoter of the human UCP2 (uncoupling protein 2 (mitochondrial, proton carrier)) was reported to be associated with risk of obesity. 28 Several polymorphisms have been described in the 5 0 -UTR of HTR1B, namely, GÀ511T,…”

Relevance and limitations of public databases for microarray design: a critical approach to gene predictions

“…For example, functional polymorphisms within the promoter sequences of APOE, PS1 and PS2 genes are associated with an increased risk of developing AD. [2][3][4] A similar involvement of the APP gene has been discussed. 5 Consequently, we have argued that genes exhibiting a differential expression between cases and controls, and located in one of the loci of interest defined by previous genome scans, could constitute potential candidate genes for AD.…”