Patient-derived hiPSC neurons with heterozygous CNTNAP2 deletions display altered neuronal gene expression and network activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102838 | GEO | 2017/08/19
SECONDARY ACCESSION(S): PRJNA399077
REPOSITORIES: GEO
Similar Datasets
Project description:Variants in CNTNAP2, a member of the neurexin family of genes that function as cell adhesion molecules, have been associated with multiple neuropsychiatric conditions such as schizophrenia, autism spectrum disorder and intellectual disability; animal studies indicate a role for CNTNAP2 in axon guidance, dendritic arborization and synaptogenesis. We previously reprogrammed fibroblasts from a family trio consisting of two carriers of heterozygous intragenic CNTNAP2 deletions into human induced pluripotent stem cells (hiPSCs) and described decreased migration in the neural progenitor cells (NPCs) differentiated from the affected CNTNAP2 carrier in this trio. Here, we report the effect of this heterozygous intragenic deletion in CNTNAP2 on global gene expression and neuronal activity in the same cohort. Our findings suggest that heterozygous CNTNAP2 deletions affect genes involved in neuronal development and neuronal activity; however, these data reflect only one family trio and therefore more deletion carriers, with a variety of genetic backgrounds, will be needed to understand the molecular mechanisms underlying CNTNAP2 deletions.
| S-EPMC5624885 | biostudies-literature
Project description:We examined whether adult heterozygous mice (Cntnap2+/-; phenotypically normal) subjected to an early-life stress would have social-related deficits and disruptions in 5-hydroxymethylcytosine (5hmC), similar to the Cntnap2-/-.
2021-12-20 | GSE87032 | GEO
Project description:Autism Spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior and communication, and restricted interests. Although various studies have been carried out to unveil the mechanisms associated with ASD, its pathophysiology is still poorly understood. Genetic variants on CNTNAP2 have been found and considered representative ASD genetic risk factors, and disruption of Cntnap2 causes ASD phenotypes in mice. Here, we performed an integrative multi-omics analysis by combining quantitative proteometabolomics data of Cntnap2 knockout (KO) mice with multi-omics data from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks of ASD. First, we found Cntnap2-associated molecular signatures and cellular processes by conducting mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex of the Cntnap2 KO mouse model. Then, we narrowed these identified processes into bona fide ASD molecular processes by incorporating multi-omics data of ASD patients' prefrontal cortex. Further, we mapped cell-type-specific ASD networks by reanalyzing single-cell RNA-seq data of forebrain organoids derived from patients with CNTNAP2 mutation. Finally, we constructed a Cntnap2-associated ASD network model consisting of mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on understanding of the Cntnap2-dependent molecular networks of ASD.
2023-03-11 | PXD031656 | Pride
Project description:Accelerated brain development is a unique feature of the human species. Not only the size but also morphology, in particular the connections between frontal cortex and basal ganglia distinguish the human brain from great apes and other primates. Recent findings suggest that structural features which may be important for language acquisition are influenced by FOXP2, key regulator of CNTNAP2. CNTNAP2 is one of the largest genes in the human genome, encompassing 2.3 Mb. It encodes a neurexin with essential roles in the vertebrate nervous system. The aim of our study was to compare the methylation patterns of CNTNAP2 in human and chimpanzee brains, assuming that epigenetic regulation is essential for brain development and human language abilities. To this end, we designed a NimbleGen tiling array covering the entire human CNTNAP2 gene plus 0.1 Mb up- and downstream flanking sequence with an average resolution of 13 bp. Methylated DNA ImmunoPreciptation (MeDIP) was used to enrich cytosine-methylated DNA fragments for downstream analysis with high-resolution tiling arrays. MeDIP-based CNTNAP2 methylation profiling
2014-02-20 | E-GEOD-52948 | biostudies-arrayexpress
Project description:Accelerated brain development is a unique feature of the human species. Not only the size but also morphology, in particular the connections between frontal cortex and basal ganglia distinguish the human brain from great apes and other primates. Recent findings suggest that structural features which may be important for language acquisition are influenced by FOXP2, key regulator of CNTNAP2. CNTNAP2 is one of the largest genes in the chimpanzee genome, encompassing 2.5 Mb. It encodes a neurexin with essential roles in the vertebrate nervous system. The aim of our study was to compare the methylation patterns of CNTNAP2 in human and chimpanzee brains, assuming that epigenetic regulation is essential for brain development and human language abilities. To this end, we designed a NimbleGen tiling array covering the entire chimpanzee CNTNAP2 gene plus 0.1 Mb up- and downstream flanking sequence with an average resolution of 13 bp. Methylated DNA ImmunoPreciptation (MeDIP) was used to enrich cytosine-methylated DNA fragments for downstream analysis with high-resolution tiling arrays. MeDIP-based CNTNAP2 methylation profiling
2014-02-20 | E-GEOD-52949 | biostudies-arrayexpress
Project description:Accelerated brain development is a unique feature of the human species. Not only the size but also morphology, in particular the connections between frontal cortex and basal ganglia distinguish the human brain from great apes and other primates. Recent findings suggest that structural features which may be important for language acquisition are influenced by FOXP2, key regulator of CNTNAP2. CNTNAP2 is one of the largest genes in the chimpanzee genome, encompassing 2.5 Mb. It encodes a neurexin with essential roles in the vertebrate nervous system. The aim of our study was to compare the methylation patterns of CNTNAP2 in human and chimpanzee brains, assuming that epigenetic regulation is essential for brain development and human language abilities. To this end, we designed a NimbleGen tiling array covering the entire chimpanzee CNTNAP2 gene plus 0.1 Mb up- and downstream flanking sequence with an average resolution of 13 bp. Methylated DNA ImmunoPreciptation (MeDIP) was used to enrich cytosine-methylated DNA fragments for downstream analysis with high-resolution tiling arrays.
2014-02-20 | GSE52949 | GEO
Project description:Accelerated brain development is a unique feature of the human species. Not only the size but also morphology, in particular the connections between frontal cortex and basal ganglia distinguish the human brain from great apes and other primates. Recent findings suggest that structural features which may be important for language acquisition are influenced by FOXP2, key regulator of CNTNAP2. CNTNAP2 is one of the largest genes in the human genome, encompassing 2.3 Mb. It encodes a neurexin with essential roles in the vertebrate nervous system. The aim of our study was to compare the methylation patterns of CNTNAP2 in human and chimpanzee brains, assuming that epigenetic regulation is essential for brain development and human language abilities. To this end, we designed a NimbleGen tiling array covering the entire human CNTNAP2 gene plus 0.1 Mb up- and downstream flanking sequence with an average resolution of 13 bp. Methylated DNA ImmunoPreciptation (MeDIP) was used to enrich cytosine-methylated DNA fragments for downstream analysis with high-resolution tiling arrays.
2014-02-20 | GSE52948 | GEO
Project description:Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, the function of CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in CNTNAP2 (affecting exons 14-15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function.
| S-EPMC4789165 | biostudies-literature
Project description:Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD expression decreased by tumor grade in all diffuse glioma subtypes, while CNTNAP2 expression was associated with diffuse glioma subtypes and with tumor grade in oligodendrogliomas and IDH wild-type astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.
2022-08-24 | GSE196707 | GEO
Project description:Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.
2023-01-12 | GSE222383 | GEO