Modeling OTUD7A loss-of-function mutation in schizophrenia-associated 15q13.3 microdeletion in human neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE189614 | GEO | 2021/11/28
REPOSITORIES: GEO
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Project description:Background: Deletions in the 15q13.3 region are associated with several neuropsychiatric disorders, including autism and schizophrenia. Association studies in humans and functional studies in mice have suggested that several genes within the 15q13.3 microdeletion may play a role in neuronal dysfunction, but the intermediate molecular mechanisms remain unknown. Methods: Induced pluripotent stem cells from 3 patients with the 15q13.3 microdeletion and 3 sex-matched controls were generated and converted into induced neurons. We analyzed the genome-wide effects of the 15q13.3 microdeletion on gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. We also evaluated gene expression changes in induced neurons containing CRISPR knockouts of single 15q13.3 microdeletion genes. Results: In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways, such as Wnt signaling, ribosome biogenesis, DNA binding, and cell adhesion. Conclusions: Our multi-omics analyses of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders. This molecular systems analysis can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.
2021-03-28 | GSE135131 | GEO
Project description:Background: The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals with intellectual disability, epilepsy, and neuropsychiatric disorders. Previous studies have investigated several genes within the deletion as potential drivers, but the pathomechanism and the underlying basis of the variable phenotype remain elusive. Methods: We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression using native RNA-seq data from blood of 3 probands with the 15q13.3 microdeletion and 4 sex- and age-matched control subjects. We assessed differentially expressed genes (DEGs), gene ontology (GO) enrichment, protein-protein interaction (PPI) functional modules, as well as gene expression in different brain developmental stages. Results: The haploinsufficiency of genes within the deleted region was not transcriptionally compensated, suggesting that a dosage effect may contribute to the pathomechanism. Although GO and PPI showed that regulation of gene expression is perturbed, we could not identify a singular driving transcription factor. We observed network-wide dysregulatory effects suggesting that the phenotype is not caused by a singular critical gene. A significant proportion of DEGs, which are silenced in the adult brain, have maximum expression during the prenatal stage of brain development. Based on DEGs and their PPI partners we identified altered functional modules related to immune and inflammatory processes, as well as nervous system development. Conclusions: We show that the 15q13.3 microdeletion has a ubiquitous impact on transcriptome pattern, especially dysregulation of genes involved in brain development. The effect on immune and inflammatory responses cannot be fully assessed based on the test material, i.e. blood. Possibly, the high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.
2022-08-08 | GSE197903 | GEO
Project description:We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness (CSNB), congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. The proband with 15q13.3 homozygous deletion and his parents with 15q13.3 heterozygous deletions described in our previous report 15 were evaluated using Affymetrix aCGH-244K arrays (build hg18). The aCGH data were validated by qPCR using primers specific to CHRNA7 as previously described. 15 The extended family and comparison subjects were also screened using the CHRNA7 primers. Immortalized lymphoblastoid lines were created from the proband, his mother, father, a paternal half sister, a paternal half brother, a paternal grandmother and two paternal great uncles. Three lymphoblastoid lines from age- and sex- matched normally developing comparison subjects with normal chromosomes were obtained from the Coriell cell repository [(AG14724 (8 yo), AG14948 (10 yo), AG14980 (9 yo)] were used for gene expression comparison with the proband. The samples from the father, mother and paternal grandmother with heterozygous 15q13.3 deletions were compared to samples from lymphoblastoid cells from adult male and female subjects respectively (normal copy number for 15q13.3 determined by qPCR).
2013-02-17 | E-GEOD-43583 | biostudies-arrayexpress
Project description:The amygdala plays a key role in the pathophysiology of depression, but the molecular mechanisms underlying amygdalar hyperactivity in depression remain unclear. In this study, we used a chronic mild stress (CMS) protocol to separate susceptible and insusceptible rat subgroups. Proteomes in the amygdalae were analyzed differentially across subgroups based on labeling with isobaric tags for relative and absolute quantitation (iTRAQ) combined with mass spectrometry. Of 2562 quantified proteins, 102 were differentially expressed. Several proteins that might be associated with the stress insusceptibility/susceptibility difference, including synapse-related proteins, were identified in the amygdala. Immunoblot analysis identified changes in VGluT1, NMDA GluN2A and GluN2B and AMPA GluA1 receptors, and PSD-95, suggesting that CMS perturbs glutamatergic transmission in the amygdala. Changes in these regulatory and structural proteins provide insight into the molecular mechanisms underlying the abnormal synaptic morphological and functional plasticity in the amygdalae of stress-susceptible rats. Interestingly, the expression level of CaMKIIβ, potentially involved in regulation of glutamatergic transmission, was significantly increased in the susceptible group. Subsequent in vitro experimentation showed that overexpression of CaMKIIβ increased the expression of PSD-95 and GluA1 in cultured hippocampal neurons. This result suggested that CaMKIIβ functions upstream from PSD-95 and GluA1 to affect LTP-based postsynaptic functional plasticity in the amygdalae of susceptible rats. Therefore, amygdalar CaMKIIβ is a potential antidepressant target. Collectively, our findings contribute to a better understanding of amygdalar synaptic plasticity in depression.
2019-01-15 | PXD044124 | iProX
Project description:Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome (PMS), autism spectrum disorders (ASDs) and intellectual disability (ID). Although a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the postsynaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the postsynaptic density (PSD) fraction from striatum and hippocampus of Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes. This unbiased approach to identify molecular disturbances at PSDs devoid of major Shank3 isoforms revealed largely distinct molecular alterations in striatum and hippocampus. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.
2017-03-08 | PXD005192 | Pride
Project description:The AMPA glutamate receptor (AMPAR) is the major type of synaptic excitatory ionotropic receptor in the brain. The most abundant AMPAR subtypes in the hippocampus are GluA1/2 and GluA2/3 heterotetramers. Each subtype contributes differentially to mechanisms of synaptic plasticity, which may be in part caused by how these receptors are regulated by specific associated proteins. A broad range of AMPAR interacting proteins have been identified and several were shown to affect biogenesis, AMPAR trafficking, and channel properties, alone or in distinct assemblies, and several revealed preferred binding to specific AMPAR subunits. To date, a systematic separate interactome analysis of the major GluA1/2 and GluA2/3 AMPAR subtypes is lacking. To reveal interactors belonging to specific AMPAR sub-complexes, we performed both quantitative and interaction proteomics on hippocampi of wildtype and GluA1- or GluA3 knock-out mice. Whereas GluA1/2 receptors co-purified TARP-γ8, PRRT1 and CNIH2 with highest abundances, GluA2/3 receptors revealed strongest co-purification of CNIH2, TARP-γ2, and OLFM1. Further analysis revealed that TARP-γ8-PRRT1 can interact directly, and co-assemble into an AMPAR subcomplex especially near the synapse.
2022-12-12 | PXD031603 | Pride
Project description:We employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins.
2022-05-02 | GSE199428 | GEO
Project description:We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness (CSNB), congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions.
2013-02-17 | GSE43583 | GEO
Project description:PTEN contains a C-terminal motif that binds to various PDZ domain-containing proteins including PSD-95. The PTEN C-terminus is known to mediate synaptic translocation of PTEN during long-term depression (LTD) and amyloid-b-induced synaptic depression. However, it remains unknown whether it regulates other synaptic functions. We compared the transcriptomic profiles of WT and PTEN C-terminus mutant brains (male) at P21. Here, we report genes that are differentially regulated in the mutant mice. This RNA-Seq analysis revealed a total of nine major differentially expressed genes (DEGs) –three upregulated and six downregulated (P < 0.05). Further gene set enrichment analysis (GSEA) of PTEN C-terminus mutant and WT transcriptomes using 5917 gene sets in the C5 (gene ontology) category revealed two strongly enriched gene ontology functions: ribosome biogenesis (positive) and transmembrane transport (negative). Our results provide a comprehensive transcriptome characterization of PTEN C-terminus mutant mice, which would provide a framework of understanding the role PTEN c-terminus in mediating various synaptic –and in larger sense, cellular –functions, and also allow thorough comparative analysis with the results of other PTEN mutant mouse lines.
2020-12-17 | GSE119236 | GEO
Project description:The postsynaptic density (PSD) is a protein condensate composed of ~1,000 proteins beneath the postsynaptic membrane of excitatory synapses. The number, shape, and plasticity of synapses are altered during development. However, the dynamics of synaptic protein composition across development have not been fully understood. Here we show alterations of PSD protein composition in mouse and primate brains during development. Proteins involved in synapse regulation are enriched in the differentially expressed (288 decreased and 267 increased) proteins on mouse PSD after a 2-week-old, which may be involved in changes of synaptic signal transduction. We find that the changes in PSD protein abundance in mouse brains correlate with gene expression levels in postnatal mice and perinatal primates. Proteome analysis of PSD from developing common marmosets (Callithrix jacchus) shows that the changes of PSD composition in mouse brain after 2-week-old occur in the marmoset brain mainly during the neonatal period and continue until adulthood. We also describe the changes of PSD proteome at the late developmental stage of marmoset, which may be involved in synaptic pruning observed in primate brains. The maturation of PSD composition is likely defective in autism spectrum disorder (ASD). Our results provide a comprehensive architecture of the remodeling of PSD composition across development, which may explain the molecular basics of synapse maturation and the pathology of psychiatric disorders, such as ASD.
2024-01-17 | PXD048549 | Pride