Analysis of the
            <i>c‐FOS</i>
            gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease

Rogaev, Evgeny I.; Lukiw, Walter J.; Vaula, Giovanna; Haines, Jonathan; Rogaeva, E.; Tsuda, Takuya; Alexandrova, N.; Liang, Yan; Mortilla, M.; Amaducci, L.; Bergamini, L; Bruni, Amalia C.; Foncin, J. F.; Macciardi, Fabìo; Montesi, M. P.; Sorbi, Sandro; Rainero, Innocenzo; Pinessi, Lorenzo; Polinsky, Ronald J.; Frommelt, Peter C.; Duara, Ranjan; Lopez, Robert; Pollen, Daniel A.; Gusella, James F.; Tanzi, R E; MacLachlan, D. Crapper; George-Hyslop, P. H. St.

doi:10.1212/wnl.43.11.2275

Cited by 21 publications

(5 citation statements)

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“…However, early on, screenings of the APP promoter in sporadic and familial early-and late-onset AD did not reveal AD-specific mutations. [34][35][36][37] More-recent studies detected a ϩ37G/C polymorphism in APP exon 1 while sequencing the Ϫ573/ϩ125 fragment of the APP promoter in 20 individuals. 38 The ϩ37 C allele was overrepresented in patients with late-onset AD who lacked apolipoprotein E (APOE) 4 alleles (frequency 17.2%), compared with elderly control individuals (10%) (odds ratio [OR] 2.08; 95% CI 1.26-3.45; adjusted for age, sex, and education).…”

mentioning

confidence: 99%

Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease

Theuns

Brouwers

Engelborghs

et al. 2006

The American Journal of Human Genetics

168

108

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Genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases. Also, expression levels of APP are essentially regulated by its core promoter and 5' upstream regulatory region and correlate with amyloid beta levels in Alzheimer disease (AD) brains. Here, we systematically sequenced the proximal promoter (-766/+204) and two functional distal regions (-2634/-2159 and -2096/-1563) of APP in two independent AD series with onset ages < or =70 years (Belgian sample, n=180; Dutch sample, n=111) and identified eight novel sequence variants. Three mutations (-118C-->A, -369C-->G, and -534G-->A) identified only in patients with AD showed, in vitro, a nearly twofold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome. These mutations either abolished (AP-2 and HES-1) or created (Oct1) transcription-factor binding sites involved in the development and differentiation of neuronal systems. Also, two of these clustered in the 200-bp region (-540/-340) of the APP promoter that showed the highest degree of species conservation. The present study provides evidence that APP-promoter mutations that significantly increase APP expression levels are associated with AD.

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mentioning

confidence: 99%

Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease

Theuns

Brouwers

Engelborghs

et al. 2006

The American Journal of Human Genetics

168

108

View full text Add to dashboard Cite

show abstract

“…Initial candidate genes in the region included FOS and HSP70 (63). Mutational analysis of the FOS gene (73,74) failed to detect mutations. Cloning and mapping of the HSPA2 gene eliminated it as a candidate (75).…”

mentioning

confidence: 99%

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

Schellenberg

1995

Proc. Natl. Acad. Sci. U.S.A.

166

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The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

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“…To screen GC-enriched regions, specific PCR and sequencing modifications were applied. 23,24 The initial analysis of the 5Ј-upstream promoter genomic region of the PSEN2 gene (accession number U50871) 25 in 10 AD and 10 non-demented individuals revealed a polymorphism caused by single nucleotide deletion at the 24914 site. To evaluate this polymorphism further the primers ps2-e1: 5Ј-taaactgtggcatacatga and ps2-e2: 5Ј-ccatacccattgagaagtt were designed for a 278-bp PCR fragment (24781-25058).…”

Section: Screening For Polymorphisms In the Psen2 Gene Promotermentioning

confidence: 99%

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

et al. 2002

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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.

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Analysis of the c‐FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease

Cited by 21 publications

References 0 publications

Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease

Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

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

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