Abstract
Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.
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Acknowledgements
We are indebted to the banque d’ADN et de cellules Pitié Salpêtrière. We thank Dr Mario Tosi and Tracey Avequin for critical reading of the manuscript and Emmanuelle Genin for statistical support. This study was funded by PHRC GMAJ 2008/067 (Rouen University Hospital).
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The investigators of the French GMAJ project include Didier Hannequin, Dominique Campion, Olivier Martinaud, Lucie Guyant-Maréchal and David Wallon (Centre Hospitalo Universitaire (CHU), Rouen); Olivier Godefroy and Candice Picard (CHU Amiens); Frédérique Etcharry-Bouyx (CHU Angers); Eric Berger (CHU Besancon); Jean-Francois Dartigues and Sophie Auriacombe (CHU Bordeaux); Vincent de la Sayette (CHU Caen); Francois Sellal (CH Colmar); Olivier Rouaud and Christelle Thauvin (CHU Dijon); Olivier Moreaud (CHU Grenoble); Stéphanie Bombois, Adeline Rollin-Sillaire, Marie-Anne Mackowiak and Florence Pasquier (CHU Lille); Isabelle Roullet-Solignac and Alain Vighetto (CHU Lyon); Mira Didic, Olivier Félician and Mathieu Ceccaldi (CHU Marseille); Audrey Gabelle and Jacques Touchon (CHU Montpellier); Martine Vercelletto and Claire Boutoleau-Bretonnière (CHU Nantes); Pierre Labauge and Giovanni Castelnovo (CHU Nimes); Claire Paquet and Jacques Hugon (CHU Lariboisière); Agnès Michon, Isabelle Le Ber and Bruno Dubois (CHU La Salpêtrière, Paris); Catherine Thomas-Antérion (CHU Saint-Etienne); Frédéric Blanc and Christine Tranchant (CHU Strasbourg); Jérémie Pariente, Michèle Puel and Jean-Francois Demonet (CHU Toulouse); Caroline Hommet and Karl Mondon (CHU Tours); Hélène Mollion and Bernard Croisile (CMRR CHU Lyon); Mathilde Sauvée (CHU Nancy); Gaelle Godenèche and Foucauld De Boisgueheneuc (CHU Poitiers).
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Rovelet-Lecrux, A., Legallic, S., Wallon, D. et al. A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease. Eur J Hum Genet 20, 613–617 (2012). https://doi.org/10.1038/ejhg.2011.225
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DOI: https://doi.org/10.1038/ejhg.2011.225
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