title: Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease.
abstract: 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.
authors: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors: Jessie
authors: J
authors: Theuns
authors: Nathalie
authors: N
authors: Brouwers
authors: Sebastiaan
authors: S
authors: Engelborghs
authors: Kristel
authors: K
authors: Sleegers
authors: Veerle
authors: V
authors: Bogaerts
authors: Ellen
authors: E
authors: Corsmit
authors: Tim
authors: T
authors: De Pooter
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Peter P
authors: PP
authors: De Deyn
authors: Christine
authors: C
authors: Van Broeckhoven