Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE20533 | GEO | 2010/05/01
SECONDARY ACCESSION(S): PRJNA125149
REPOSITORIES: GEO
Similar Datasets
Project description:Shank2 is an abundant excitatory postsynaptic scaffolding protein implicated in neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability, developmental delay, and schizophrenia. Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-HM mice) show ASD-like behavioral deficits and altered synaptic functions, although little is known about how different brain regions contribute to Shank2-mutant phenotypes. Here we attempted transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank2-heterozygous/HT and Shank2-homozygous/HM mice. The mutant cortex, hippocampus, and striatum displayed distinct sets of differentially expressed genes associated with neuronal and synaptic functions in a gene dosage-differential manner. Gene set enrichment analyses of cortical Shank2-HT transcripts revealed increased synaptic gene expression and transcriptomic changes that are opposite to those observed in ASD (reverse-ASD), whereas cortical Shank2-HM transcripts displayed decreased synaptic gene expression and ASD-like transcriptomic patterns. The hippocampal Shank2-HT transcripts displayed minimally altered synaptic gene expression and mixed ASD-like and reverse-ASD patterns, whereas the Shank2-HM-hippocampus showed increased synaptic gene expression and reverse-ASD patterns. The striatal Shank2-HT/HM transcriptomes were largely similar to the hippocampal transcriptomes, although the main changes were observed in cell-type-specific genes, unlike the hippocampal changes mainly involving ASD-related/risk genes. These results indicate that heterozygous and homozygous Shank2 deletions in mice lead to brain region- and gene dosage-differential transcriptomic changes.
2022-11-02 | GSE200439 | GEO
Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in total synapse number and dendrite complexity. Dendrite length increases were exacerbated by IGF1 or BDNF treatment. Increased excitatory synapse function in haploinsufficient SHANK2 neurons was phenocopied in gene-edited knockout SHANK2 neurons. Gene correction of an ASD SHANK2 mutation rescued excitatory synapse function supporting a role for SHANK2 as a negative regulator of connectivity in developing human neurons. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synaptic and plasticity gene sets and ASD gene modules, and activity dependent dendrite extension was defective. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
2019-02-04 | GSE122550 | GEO
Project description:Shank2 is an abundant postsynaptic scaffolding protein known to regulate excitatory synaptic assembly and function and is implicated in autism spectrum disorders (ASD). Whereas patient Shank2 mutations in autistic individuals are heterozygous, Shank2 functions studied in mice have mainly relied on the results from homozygous mutant mice, largely because of relatively strong synaptic and behavioral phenotypes. Moreover, although synaptic changes at juvenile and adult Shank2-mutant mice seem to be largely similar, it remains unclear whether there are any age-dependent changes across these stages at the molecular level. To address these questions, we attempted RNA-Seq analyses of the transcriptomes in the prefrontal cortex of both heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile and adult stages. The results indicate that heterozygous, but not homozygous, juvenile Shank2-mutant mice show strong transcriptomic changes that promote excitatory synaptic transmission and suppress ASD-related gene expressions. In contrast, adult Shank2-mutant mice show largely similar and dosage-dependent transcriptomic changes.
2021-05-27 | GSE168211 | GEO
Project description:Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASD). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 show decreased NMDA receptor (NMDAR) functions and autistic-like behaviors in juvenile (~postnatal day or P21) and adult (> P56) stages that are rescued by NMDAR activation. These mice, however, show an opposite change increased NMDAR functions—at ~P14, and NMDAR suppression by early and chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at juvenile (~P21) and adult (~P56) stages. To explore molecular mechanisms underlying the long-lasting effects of early memantine treatment, we performed RNA-Seq analysis of forebrains from wild-type and Shank2-mutant mice early and chronically treated with vehicle or memantine. Memantine-treated Shank2-mutant mice showed upregulations of chromatin-related genes and downregulations of mitochondria- and ribosome-related genes. In addition, vehicle-treated Shank2-mutant mice showed transcriptomic patterns that are largely opposite to those observed in ASD, as supported by the expression patterns of ASD-risk/related genes and cell-type-specific genes. These patterns, likely representing compensatory changes, were weakened by early memantine treatment. These results suggest that early chronic memantine treatment in Shank2-mutant mice alters chromatin- and mitochondria/ribosome-related gene expressions and weakens anti-ASD transcriptomic patterns.
2021-10-06 | GSE171931 | GEO
Project description:The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically-detectable chromosomal abnormalities are the most frequent recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy number variants. We studied 100 children with idiopathic mental retardation and their parents using the Affymetrix GeneChip® Mapping 100K Assay and found de novo duplications as small as 1.1 Mb in three cases, de novo deletions as small as 178 kb in eight cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy number variants as conventional cytogenetic analysis in people with mental retardation. Experiment Overall Design: Using the Affymetrix GeneChip® Mapping 100K Assay we studied 100 trios that each included one child with idiopathic mental retardation (MR) and both of his/her unaffected biological parents. We also tested 10 unaffected siblings of the MR children from 10 of the above families. In addition, we analyzed 7 trios (child and both unaffected biological parents) as positive controls with previously identified chromosomal aberrations. Experiment Overall Design: Within each sample ID the four digit number refers to a family. Following this four digit family number, 'c' indicates child with MR, 'm' means unaffected mother, 'f' means unaffected father and 's' means unaffected sibling.
2008-06-21 | E-GEOD-7226 | biostudies-arrayexpress
Project description:Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
2017-01-24 | GSE79824 | GEO
Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
| EGAS00001003436 | EGA
Project description:The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically-detectable chromosomal abnormalities are the most frequent recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy number variants. We studied 100 children with idiopathic mental retardation and their parents using the Affymetrix GeneChip® Mapping 100K Assay and found de novo duplications as small as 1.1 Mb in three cases, de novo deletions as small as 178 kb in eight cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy number variants as conventional cytogenetic analysis in people with mental retardation. Keywords: mental retardation, trio analysis, copy number variant, CNV, chromosome aberration, array CGH
2007-03-12 | GSE7226 | GEO
Project description:Background: Mental Retardation occurs with the prevalence of 2%-3% of general population. Molecular karyotyping by 1-Mb resolution microarray revealed that pathological genomic imbalances were found in 14%-20% of MR. Aim: The aim of this study is to find the submicroscopic rearrangements in patient with MR using the custom BAC microarray (probe spacing at 0.75 Mb throughout the human genome). Conclusion: We identified approximate 2.0-Mb deletion on 9q33.3-q34.11 in a female with MR (Patient 1). Keywords: array CGH
2008-05-11 | GSE10077 | GEO
Project description:Autism spectrum disorders (ASDs) are thought to involve diverse neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to play important roles in the development of autistic-like phenotypes is unclear. Here, we show that early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like phenotypes in adult mice. Shank2–/– mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier pre-weaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 is rapidly shifted to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction in Shank2–/– mice by the NMDAR antagonist memantine before weaning (P7–21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). In addition, early memantine treatment of Shank2–/– mice substantially alters transcription of numerous genes, driving gene expression patterns in a direction largely opposite that observed in drug-untreated Shank2–/– mice, which, interestingly, mimic those observed in autistic individuals. These results suggest that early NMDAR hyperfunction in Shank2–/– mice leads to late NMDAR hypofunction and autistic-like behaviors, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages. This SuperSeries is composed of the SubSeries listed below.
2021-04-20 | GSE97896 | GEO