Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
Details
Serval ID
serval:BIB_43AF3958B4FF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
Journal
PLoS genetics
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Publication state
Published
Issued date
02/2012
Peer-reviewed
Oui
Volume
8
Number
2
Pages
e1002521
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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
Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Signal Transducing/metabolism, Adult, Alternative Splicing/genetics, Cell Line, Child, Child Development Disorders, Pervasive/genetics, Child, Preschool, Female, Gene Dosage/genetics, Gene Expression Regulation, Humans, Male, Nerve Tissue Proteins/genetics, Neurons/cytology, Protein Isoforms/genetics, Protein Isoforms/metabolism, RNA Splice Sites/genetics, Receptors, Nicotinic/genetics, Receptors, Nicotinic/metabolism, Sequence Deletion/genetics, Synapses/genetics, Synapses/pathology, Tissue Distribution, alpha7 Nicotinic Acetylcholine Receptor
Pubmed
Web of science
Open Access
Yes
Create date
15/08/2019 9:29
Last modification date
03/09/2019 5:26