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A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

ABSTRACT: A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

PROVIDER: PRJNA823698 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18645309.fastq.gz	Fastqsanger.gz
	SRR18645310_1.fastq.gz	Fastqsanger.gz
	SRR18645310_2.fastq.gz	Fastqsanger.gz
	SRR18645311.fastq.gz	Fastqsanger.gz
	SRR18645312.fastq.gz	Fastqsanger.gz

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A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

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

A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

Project description:The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital, cognitive, and neuropsychiatric anomalies in patients. The clinical presentation of the disease phenotypes is variable, posing significant challenges for prognosis of inheritance risk and clinical outcomes for the CNV carriers. ~85% of patients and almost all available human-centered models of this condition reflect the ~2.7 Mb “A-D” deletion at this locus. Leveraging a CRISPR/Cas9-based engineering strategy and induced pluripotent stems cells, we generated novel isogenic models for the smaller, commonly inherited 1.5 Mb “A-B” deletion found in ~5-10% of 22q11.2DS patients. The bulk RNA-seq data included here reflects paired-end 100 bp sequencing of iPSC-derived neuronal progenitor cells and excitatory neurons. These data reflect three independent clones either carrying the designed 22q11.2 deletion or control comparators (2 clones nucleofected with same sgRNA but with no deletion generated; 1 clone derived from the parental Cas9-expressing iPSC line). We anticipate that these novel, isogenic models will carry significant utility for the study of 22q11.2 deletion syndrome.

2022-05-02 | GSE200225 | GEO

Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

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

22q11.2 deletion syndrome human cortical organoids

Project description:We derived iPSC from individuals carrying a 22q11.2 deletion and controls and differentiated them into 3D cortical organoids.

2020-07-08 | GSE142041 | GEO

Single-nucleus RNA sequencing of OCTN2-defective engineered heart tissues and isogenic control

Project description:Primary carnitine deficiency (PCD) is an autosomal recessive disorder caused by mutations in the gene SLC22A5, encoding for the plasmalemmal carnitine transporter OCTN2. PCD patients suffer from muscular weakness and dilated cardiomyopathy (DCM). However, currently available PCD models were unable to distinguish causative from secondary pathomechanisms. To further understand the contribution of cellular subclusters to the PCD disease phenotype we analyzed engineered heart tissues from OCTN2-defective genotype in comparison to isogenic control using single-nucleus RNA sequencing.

2022-08-22 | GSE211650 | GEO

Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

Project description:Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

| PRJNA1029625 | ENA

Single-nucleus RNA sequencing of OCTN2-defective engineered heart tissues and isogenic control

Project description:Single-nucleus RNA sequencing of OCTN2-defective engineered heart tissues and isogenic control

| PRJNA871255 | ENA

22q11.2 deletion syndrome human cortical organoids

Project description:22q11.2 deletion syndrome human cortical organoids

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Neuronal Defects in a Human Cellular Model of 22q11.2 Deletion Syndrome

Project description:22q11.2 deletion syndrome (22q11DS) is a common cause of developmental neuropsychiatric disorders, including psychosis, autism and epilepsy. This highly penetrant genetic syndrome provides a unique opportunity to mitigate the challenges raised by the heterogeneity of complex mental disorders and to identify specific neuronal phenotypes. Here, we generated induced pluripotent stem cells from subjects carrying a 3 Mb deletion at the 22q11.2 locus and from controls and differentiated these cells in vitro into three-dimensional organoid resembling the developing cerebral cortex. We performed single-cell RNA-sequencing to establish the reliability and reproducibility of cortical organoid differentiation in 22q11DS.

2020-07-08 | GSE145122 | GEO

MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and 22q11.2 deletion

Project description:We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ) -associated genetic factor. Several genes in the deleted region have been implicated; one of the more promising candidates is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. miRNA profiling of 7 SZ samples and 9 Control samples derived from iPSCs

2015-08-01 | E-GEOD-65367 | biostudies-arrayexpress

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