首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders
Authors:Leblond Claire S  Heinrich Jutta  Delorme Richard  Proepper Christian  Betancur Catalina  Huguet Guillaume  Konyukh Marina  Chaste Pauline  Ey Elodie  Rastam Maria  Anckarsäter Henrik  Nygren Gudrun  Gillberg I Carina  Melke Jonas  Toro Roberto  Regnault Beatrice  Fauchereau Fabien  Mercati Oriane  Lemière Nathalie  Skuse David  Poot Martin  Holt Richard  Monaco Anthony P  Järvelä Irma  Kantojärvi Katri  Vanhala Raija  Curran Sarah  Collier David A  Bolton Patrick  Chiocchetti Andreas  Klauck Sabine M  Poustka Fritz  Freitag Christine M  Waltes Regina  Kopp Marnie  Duketis Eftichia  Bacchelli Elena  Minopoli Fiorella
Institution:Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
Abstract: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.
Keywords:
本文献已被 PubMed 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号