TY  - JOUR
A1  - Leblond, Claire S.
A1  - Heinrich, Jutta
A1  - Delorme, Richard
A1  - Proepper, Christian
A1  - Betancur, Catalina
A1  - Huguet, Guillaume
A1  - Konyukh, Marina
A1  - Chaste, Pauline
A1  - Ey, Elodie
A1  - Rastam, Maria
A1  - Anckarsäter, Henrik
A1  - Nygren, Gudrun
A1  - Gillberg, I. Carina
A1  - Melke, Jonas
A1  - Toro, Roberto
A1  - Regnault, Beatrice
A1  - Fauchereau, Fabien
A1  - Mercati, Oriane
A1  - Lemière, Nathalie
A1  - Skuse, David
A1  - Poot, Martin
A1  - Holt, Richard
A1  - Monaco, Anthony P.
A1  - Järvelä, Irma
A1  - Kantojärvi, Katri
A1  - Vanhala, Raija
A1  - Curran, Sarah
A1  - Collier, David A.
A1  - Bolton, Patrick F.
A1  - Geburtig-Chiocchetti, Andreas
A1  - Klauck, Sabine M.
A1  - Poustka, Fritz
A1  - Freitag, Christine M.
A1  - Waltes, Regina
A1  - Kopp, Marnie
A1  - Duketis, Eftichia
A1  - Bacchelli, Elena
A1  - Minopoli, Fiorella
A1  - Ruta, Liliana
A1  - Battaglia, Agatino
A1  - Mazzone, Luigi
A1  - Maestrini, Elena
A1  - Sequeira, Ana F.
A1  - Oliveira, Barbara
A1  - Vicente, Astrid M.
A1  - Oliveira, Guiomar
A1  - Pinto, Dalila
A1  - Scherer, Stephen W.
A1  - Zelenika, Diana
A1  - Delepine, Marc
A1  - Lathrop, Mark
A1  - Bonneau, Dominique
A1  - Guinchat, Vincent
A1  - Devillard, Françoise
A1  - Assouline, Brigitte
A1  - Mouren, Marie-Christine
A1  - Leboyer, Marion
A1  - Gillberg, Christopher
A1  - Böckers, Tobias M.
A1  - Bourgeron, Thomas
T1  - Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of Autism spectrum disorders
T2  - PLoS Genetics, volume 8, issue 2, e1002521 (2012)
N2  - Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/25001
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-250017
SN  - 1553-7404
SN  - 1553-7390
VL  - 8
IS  - (2): e1002521
PB  - Public Library of Science
CY  - San Francisco, Calif.
ER  -