A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

Anne Rovelet-Lecrux; Solenn Legallic; David Wallon; Jean-Michel Flaman; Olivier Martinaud; Stéphanie Bombois; Adeline Rollin-Sillaire; Agnès Michon; Isabelle Le Ber; Jérémie Pariente; Michèle Puel; Claire Paquet; Bernard Croisile; Catherine Thomas-Antérion; Martine Vercelletto; Richard Lévy; Thierry Frébourg; Didier Hannequin; Dominique Campion; Non Renseigné; Olivier Moreaud

doi:10.1038/ejhg.2011.225

Journal articles

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

Anne Rovelet-Lecrux ¹ Solenn Legallic ² David Wallon Jean-Michel Flaman Olivier Martinaud ³ Stéphanie Bombois ⁴ Adeline Rollin-Sillaire Agnès Michon Isabelle Le Ber ⁵ Jérémie Pariente ⁶ Michèle Puel ^{6, 7} Claire Paquet ⁸ Bernard Croisile ⁹ Catherine Thomas-Antérion ¹⁰ Martine Vercelletto ¹¹ Richard Lévy ¹² Thierry Frébourg ¹³ Didier Hannequin ¹³ Dominique Campion ¹⁴ Non Renseigné Olivier Moreaud ^{15, 16}

1 Service de neurologie [Rouen]

2 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques

3 CHU Rouen

4 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837

5 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière

6 ICHN - Imagerie cérébrale et handicaps neurologiques

7 Neurologie générale et maladies inflammatoires du système nerveux [Toulouse]

8 Institut du Fer à Moulin

9 Département de Neurologie

10 CMRR - Centre de Mémoire de Ressource et Recherche

11 Service de neurologie [Nantes]

12 Neuro-anatomie fonctionnelle du comportement et de ses troubles

13 GMFC - Génétique du cancer et des maladies neuropsychiatriques

14 Service de neurologie [Rouen]

15 LPNC - Laboratoire de Psychologie et NeuroCognition

16 Unité de Neuropsychologie

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Neurons and Cognition [q-bio.NC]

Complete list of metadatas

https://hal.archives-ouvertes.fr/hal-00965208
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Submitted on : Monday, March 24, 2014 - 6:35:50 PM
Last modification on : Thursday, January 14, 2021 - 11:10:02 AM

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

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A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

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