Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Intellectual disability and mood disorder associated with partial deletion of the Neurexin 1 Gene

ABSTRACT: Abstract Background Neurexins are proteins located in the presynaptic membrane that bind postsynaptic ligands, neuroligins, neurexophilins, and dystrophoglycan. They exert profound effects on neurological function by mediating signalling across synapses and determining synaptic characteristics through the recruitment of additional proteins for synapse formation. Alterations in neurexin-encoding genes cause cognitive disorders such as autism, developmental delay and schizophrenia. The three neurexin genes in the human genome (NRXN1, NRXN2, and NRXN3) each have two different functional promoters, producing a large (alpha) and small (beta) transcript with corresponding proteins. NRXN1 produces hundreds, perhaps thousands, of different transcripts with differential localization in the CNS. Results We report here the identification of an individual (53825) with mild dysmorphia, severe language disorder, mild intellectual disability, attention deficit hyperactivity disorder (ADHD), and a mood disorder. Genomic analysis by Affymetrix 6.0 Gene Chip and FISH (fluorescence in situ hybridization) using probes specific for NRXN1 revealed a hemizygous deletion of approximately 190 Kb, which includes exons 3-5 of NRXN1. This deletion should result in the absence of the vast majority of different NRXN1 alpha transcripts from one of the NRXN1 gene copies, without effecting NRXN1 beta transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23358 | GEO | 2011/06/25

SECONDARY ACCESSION(S): PRJNA131449

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Intellectual disability and mood disorder associated with partial deletion of the Neurexin 1 Gene

Project description:Abstract Background Neurexins are proteins located in the presynaptic membrane that bind postsynaptic ligands, neuroligins, neurexophilins, and dystrophoglycan. They exert profound effects on neurological function by mediating signalling across synapses and determining synaptic characteristics through the recruitment of additional proteins for synapse formation. Alterations in neurexin-encoding genes cause cognitive disorders such as autism, developmental delay and schizophrenia. The three neurexin genes in the human genome (NRXN1, NRXN2, and NRXN3) each have two different functional promoters, producing a large (alpha) and small (beta) transcript with corresponding proteins. NRXN1 produces hundreds, perhaps thousands, of different transcripts with differential localization in the CNS. Results We report here the identification of an individual (53825) with mild dysmorphia, severe language disorder, mild intellectual disability, attention deficit hyperactivity disorder (ADHD), and a mood disorder. Genomic analysis by Affymetrix 6.0 Gene Chip and FISH (fluorescence in situ hybridization) using probes specific for NRXN1 revealed a hemizygous deletion of approximately 190 Kb, which includes exons 3-5 of NRXN1. This deletion should result in the absence of the vast majority of different NRXN1 alpha transcripts from one of the NRXN1 gene copies, without effecting NRXN1 beta transcription. Copy number analysis of Affymetrix 6.0 SNP arrays was performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples for pediatric patients. One sample showed partial deletion of NRXN1 alpha; data presented in this Series.

2011-06-24 | E-GEOD-23358 | biostudies-arrayexpress

Single-cell RNAseq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles

Project description:Neurexins are key synaptic organizers which exist in thousands of alternatively spliced isoforms. Because trans-synaptic neurexin interactions with different post-synaptic molecules are largely isoform dependent, a cell type-level census of different neurexin isoforms could predict molecular interactions relating to synapse identity and function. Using single-cell transcriptomics to study the origin of neurexin diversity in multiple murine hippocampal and cortical cell types, we have discovered shared expression patterns in developmentally-related cell types. By comparing neurexin profiles in immature embryonic neurons, we show that neurexin profiles are specified during early development and remain unchanged throughout neuronal maturation. In contrast to this, we find that expression of other cell-adhesion molecules is modulated throughout circuit maturation. Thus, our findings reveal that ontogenetic stability of neurexin expression is unique among the broader landscape of cell-adhesion molecules, whose coordinated expression progressively governs the emergence of cell type identity.

2019-06-23 | GSE121653 | GEO

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Project description:Autism spectrum disorders (ASD) are common, heritable neurodevelopmental conditions. The genetic architecture of ASD is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASD by using Affymetrix 10K single nucleotide polymorphism (SNP) arrays and 1168 families with = 2 affected individuals to perform the largest linkage scan to date, while also analyzing copy number variation (CNV) in these families. Linkage and CNV analyses implicate chromosome 11p12-p13 and neurexins, respectively, amongst other candidate loci. Neurexins team with previously-implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for ASD. Keywords: Autism spectrum disorder, Affymetrix SNP genotyping, linkage analysis, copy number analysis, chromosomal rearrangements.

2007-02-20 | GSE6754 | GEO

LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

Project description:Synapses are organized into nanocolumns that control neurotransmission efficacy through precise alignment of postsynaptic AMPARs and presynaptic release sites. How these are trans-synaptically arranged remains elusive, despite evidence involving adhesion proteins. Highly enriched and confined at synapses, Leucine-Rich Repeat Transmembrane protein LRRTM2, is ideally poised to play this role by interacting with presynaptic Neurexins. Recent evidence show that LRRTM2 interacts with Neurexins through the C-terminal cap of LRRTM2 extracellular domain, but the role of this binding interface containing E348 has not been explored in synapse formation and function. Here, we developed a conditional knock-out mouse model (cKO) to address these questions and iden-tify LRRTM2 as a critical regulator of synapse nano-organization. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function. Surface expression, synaptic clustering, and membrane diffusion are tightly controlled by different motifs in LRRTM2 C-terminal domain, while the N-terminal domain controls pre-synapse nano-organization, AMPARs sub-positioning and stabilization, through the recently identified Neurexin-binding interface. Thus, LRRTM2 appears as a central organizer of synapse nanostructure through interaction with presynaptic Neurexins.

2024-09-18 | PXD054623 | Pride

Impaired locomotor behavior of C. elegans neuroligin mutants is dependent of the catechol-O-methyltransferase COMT-4

Project description:Neuroligins are neuronal membrane adhesion molecules that have been involved in neuro-psychiatric and neuro-developmental disorders. They interact with neurexins and other specific proteins in the synaptic cleft. The nlg-1 gene of Caenorhabditis elegans encodes NLG-1, an ortholog of human neuroligins. NLG-1 is involved in dopaminergic and serotoninergic signaling that controls the locomotory rate of the nematode. When well fed animals are transferred to a plate with food (bacterial lawn) they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, food deprived animals when moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR) is serotonin dependent. C. elegans nlg-1- deficient mutants are impaired in BSR, ESR and other locomotory behaviors such as gentle touch response. Here we report that nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme that presumably has catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants recovers wild type phenotypes of BSR, ESR and gentle touch responses. Based on these results we propose a model for the neuroligin function in modulating the dopamine-dependent locomotory behavior in the nematode.

2018-05-31 | GSE97980 | GEO

A Specific Neuroligin3-αNeurexin1Signaling Regulates GABAergic Synaptic Function in Mouse Hippocampus

Project description:Synapses are fundamental organizers of precise signal propagation between neurons. Maintaining synapse assemblies require interactions between pre- and post- synaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the function of Neuroligins (Nlgn1 - 4), postsynaptic CAMs, relies on the formation of trans-synaptic complexes with Neurexins (Nrxs), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated through Nrx interaction is mostly unknown. Here, we find for the first time that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3 (VGT3)-expressing inhibitory terminals. Overexpression and knockdown approaches indicate that Nlgn3 regulates VGT3-positive inhibitory interneuron-mediated synaptic transmission. Fluorescent in situ hybridization and single-cell RNA sequencing studies revealed that αNrxn1 and βNrxn3 are VGT3 interneuron-specific Nrxn isoforms and the expression levels of Nrxn splice isoforms are highly diverse in VGT3 interneurons, respectively. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrx1+AS4 expressed in VGT3-positive interneurons to regulate inhibitory synaptic transmission. Our results strongly suggest that specific Nlgn-Nrx interaction generate distinct functional properties at synapses.

2021-01-04 | GSE150989 | GEO

Differential Gene Expression in Patients with Mood Disorders

Project description:RNA was extracted from peripheral blood mononuclear cells (PBMC) of 24 adult healthy controls, 8 adult patients with bipolar disorder, and 21 adult patients with major depressive disorder to analyze gene expression patterns that identify biomarkers of disease and that may be correlated with fMRI data.

2012-07-26 | GSE39653 | GEO

Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-Derived NRXN1-Mutant Neurons

Project description:Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and predispose to multiple other neurodevelopmental disorders. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

2021-03-12 | GSE168762 | GEO

Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia

Project description:Total of 56 microglia samples from postmortem brain tissue of four different brain regions, medial frontal gyrus (MFG), superior temporal gyrus (STG), subventricular zone (SVZ) and thalamus (THA), of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array to characterize the DNA methylation landscape of human microglia and the factors that contribute to variations in the microglia methylome

2022-01-31 | GSE191200 | GEO

Homo sapiens

Project description:Intellectual disability and mood disorder associated with partial deletion of the Neurexin 1 Gene

| PRJNA131449 | ENA