Neuronal Defects in a Human Cellular Model of 22q11.2 Deletion Syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145122 | GEO | 2020/07/08
REPOSITORIES: GEO
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Project description:22q11.2 Deletion Syndrome (22q11DS) represents one of the most common known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes. Eighty percent of 22q11DS individuals (n=37) carried the typical 3 Mb deletion, with significant variability in the deletion characteristics in the remainder of the sample (n=9). Both analysis of differential expression and weighted gene coexpression network analysis (WGCNA) identified peripheral changes in gene expression related to psychotic symptom expression in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. Remarkably, this 22q11DS psychosis module was significantly enriched for brain-expressed genes, was not related to antipsychotic medication use, and showed significant overlap with transcriptional changes occurring in idiopathic schizophrenia in an independent dataset. In those with 22q11DS-ASD, both differential expression and WGCNA analyses pointed towards dysregulation of immune response pathways. The ASD-associated module showed overlap with a neuronal module enriched for known autism susceptibility genes identified in brain transcriptome data from individuals with idiopathic autism. These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD, warranting their further investigation in idiopathic illness. Participants. Forty-six patients with a molecularly confirmed diagnosis of a 22q11.2 deletion and 66 controls (24 unrelated controls and 42 first-degree relatives of 22q11DS patients) were recruited from an ongoing longitudinal study. Comparative Genomic Hybridization Arrays. To characterize the boundaries of the 22q11.2 deletion, we designed a custom NimbleGen 12*135 HX12 array. Microarray-based gene expression analysis. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays.Gene ontology annotation was performed using DAVID (http://david.abcc.ncifcrf.gov/) and pathway analysis was performed by using the Functional Analysis Annotation tool in the Ingenuity Pathways Analysis (IPA) software (Ingenuity Systems, www.ingenuity.com). Because the healthy control group included parents of 22q11DS patients, there were significant age differences between groups (Table 1, p<.001); thus, we corrected for age in all analyses.Weighted Gene Co-expression Network Analysis (WGCNA). We conducted WGCNA, a systems biology approach used to identify networks of co-expressed genes in relation to phenotypic data, using the R package. Phenotypic traits examined within the 22q11DS group included: categorical and dimensional indicators of psychosis (i.e. psychosis diagnosis and SIPS psychotic symptom severity score), ASD, and gender. For modules that showed a statistically significant relationship with any phenotypic trait (p<.05), GO analyses and IPA were conducted. Validation with published datasets. In order to validate our gene expression and WGCNA results, we overlapped gene lists obtained from microarray differential expression analysis for 22q11DS vs. Controls,
2015-09-01 | E-GEOD-59216 | biostudies-arrayexpress
Project description:22q11.2 Deletion Syndrome (22q11DS) represents one of the most common known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes. Eighty percent of 22q11DS individuals (n=37) carried the typical 3 Mb deletion, with significant variability in the deletion characteristics in the remainder of the sample (n=9). Both analysis of differential expression and weighted gene coexpression network analysis (WGCNA) identified peripheral changes in gene expression related to psychotic symptom expression in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. Remarkably, this 22q11DS psychosis module was significantly enriched for brain-expressed genes, was not related to antipsychotic medication use, and showed significant overlap with transcriptional changes occurring in idiopathic schizophrenia in an independent dataset. In those with 22q11DS-ASD, both differential expression and WGCNA analyses pointed towards dysregulation of immune response pathways. The ASD-associated module showed overlap with a neuronal module enriched for known autism susceptibility genes identified in brain transcriptome data from individuals with idiopathic autism. These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD, warranting their further investigation in idiopathic illness.
2015-09-01 | GSE59216 | GEO
Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.
2016-10-10 | GSE73981 | GEO
Project description:22q11.2 deletion syndrome (22q11DS) substantially increases the risk of cognitive decline and psychiatric disease. However, neuroanatomic changes in 22q11DS are of a subtle-to-moderate degree and their connection to brain function is not clear. Here we report a severe (~70%) and specific reduction (dysplasia) of two cerebellar lobules, paraflocculus and flocculus (PF/F) and associated deficits in vestibulo-ocular reflex (VOR) in mouse models of 22q11DS (22q11DS mice). A specific but less severe PF/F dysplasia was confirmed in humans with 22q11DS. Tbx1 haploinsufficiency recapitulated the PF/F and VOR deficits in 22q11DS mice. The 22q11DS-associated PF/F dysplasia was not due to altered neural composition or neurogenesis. Rather, a part of temporal bone called subarcuate fossa (SF), which encapsulates the PF/F, and semicircular canals of the inner ear, which connects to the SF were malformed in 22q11DS and Tbx1-deficientmice. Our single-nuclei RNA Sequencing and immunohistochemistry data revealed that Tbx1 haploinsufficiency caused precocious differentiation of chondrocyte to osteoblasts in the petrous bone, but no changes in cell type compositions in the PF/F. These data suggest a novel structure-function pathogenic interrelationship in 22q11DS, where Tbx1 haploinsufficiency causes a skeletal deformity occluding cerebellar development and resulting in motor learning deficiency.
2024-09-19 | GSE254044 | GEO
Project description:22q11.2 deletion syndrome human cortical organoids
| PRJNA595613 | ENA
Project description:The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital and neuropsychiatric anomalies. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPSC models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ~1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ~2.7 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion markers. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found decreased proliferation and accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest potential pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.
2023-05-11 | PXD032075 | Pride
Project description:Velo-cardio-facial syndrome/DiGeorge syndrome/22q11.2 deletion syndrome (22q11DS) patients have a submucous cleft palate, velo-pharyngeal insufficiency associated with hypernasal speech, facial muscle hypotonia and feeding difficulties. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on 22q11.2, results in a cleft palate and a reduction or loss of branchiomeric muscles. To identify genes downstream of Tbx1 for myogenesis, gene profiling was performed on mandibular arches (MdPA1) from Tbx1+/+ and Tbx1-/- mouse embryos.
2014-05-21 | GSE35013 | GEO
Project description:Velo-cardio-facial syndrome/DiGeorge syndrome/22q11.2 deletion syndrome (22q11DS) patients have a submucous cleft palate, velo-pharyngeal insufficiency associated with hypernasal speech, facial muscle hypotonia and feeding difficulties. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on 22q11.2, results in a cleft palate and a reduction or loss of branchiomeric muscles. To identify genes downstream of Tbx1 for myogenesis, gene profiling was performed on mandibular arches (MdPA1) from Tbx1+/+ and Tbx1-/- mouse embryos.
2014-05-21 | GSE30980 | GEO
Project description:Purpose: 22q11 Deletion Syndrome (22q11DS) is a disorder caused by a heterozygous deletion of 3 million base pairs containing approximately 50 known genes on chromosome 22q. It occurs in around 1 in 4,000 live births. The common phenotypes of 22q11DS include a large spectrum of congenital anomalies, most notably of the cardiovascular system as well as several developmental neuropsychiatric disorders, in particular schizophrenia and autism spectrum disorders.Here we are testing the hypothesis that, in addition to changing the gene dosage of genes located within the CNV boundaries, large CNVs may have an effect on long-range chromosome interactions and epigenetic profiles. Methods: We generated Hi-C contact maps for 11 human lymphoblastoid cell lines and performed RNA-Seq on 14 cell lines and ChIP-seq of H3K27ac, H3K27me3 and CTCF for some of the cell lines. Results: We found dosage effects of 22q11del on chromosome contacts, epigenetic profiles and gene expressions. Extensive changes on these levels caused by 22q11del are global instead of confined to the deletion region only. Conclusions: Our results shed light on the comprehensive effects of 22q11del on different molecular levels in lymphoblastoid cell lines.
2017-09-05 | GSE76922 | GEO
Project description:Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.
2024-02-22 | GSE245719 | GEO