University of Chicago Press - AD-Associated A...

Am. J Hum. Genet., 78: 936–946, 2006© 2006 by The American Society of Human Genetics. All rights reserved.
0002-9297/2006/7806-0005$15.00
DOI: 10.1086/504044
Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease
Jessie Theuns,1,2,4
Nathalie Brouwers,1,2,4
Sebastiaan Engelborghs,3,4,5
Kristel Sleegers,1,2,4
Veerle Bogaerts,1,2,4
Ellen Corsmit,1,2,4
Tim De Pooter,1,2,4
Cornelia M. van Duijn,6
Peter P. De Deyn,2,4,5 and
Christine Van Broeckhoven1,2,4
1Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, Laboratories of 2Neurogenetics and 3Neurochemistry and Behavior, Institute Born-Bunge, 4University of Antwerp, and 5Memory Clinic, Department of Neurology, Middelheim General Hospital, Antwerp; and 6Epidemiology and Biostatistics Department, Erasmus Medical Center, Rotterdam
Received November 28, 2005; accepted for publication March 8, 2006; electronically published April 10, 2006.
Address for correspondence and reprints: Dr. Christine Van Broeckhoven, Neurodegenerative Brain Diseases Group, VIB8–Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium. E-mail:christine.vanbroeckhoven@ua.ac.be
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 β 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 ages70 years (Belgian sample,; Dutch sample,) 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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Petra Nowotny, Xavier Simcock, Sarah Bertelsen, Anthony L. Hinrichs, John S.K. Kauwe, Kevin Mayo, Scott Smemo, John C. Morris, Alison Goate. (2007) Association studies testing for risk for late-onset Alzheimer's disease with common variants in the β-amyloid precursor protein (APP). American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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A. P. Grigorenko, E. I. Rogaev. (2007) Molecular basis of Alzheimer’s disease. Molecular Biology 41:2, 294
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