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https://www.readbyqxmd.com/read/28325891/whole-exome-sequencing-identifies-a-novel-de-novo-mutation-in-dync1h1-in-epileptic-encephalopathies
#1
Zhongdong Lin, Zhenwei Liu, Xiucui Li, Feng Li, Ying Hu, Bingyu Chen, Zhen Wang, Yong Liu
Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322282/maternal-immune-activation-dysregulation-of-the-fetal-brain-transcriptome-and-relevance-to-the-pathophysiology-of-autism-spectrum-disorder
#2
M V Lombardo, H M Moon, J Su, T D Palmer, E Courchesne, T Pramparo
Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28321286/crispr-cas9-mediated-heterozygous-knockout-of-the-autism-gene-chd8-and-characterization-of-its-transcriptional-networks-in-cerebral-organoids-derived-from-ips-cells
#3
Ping Wang, Ryan Mokhtari, Erika Pedrosa, Michael Kirschenbaum, Can Bayrak, Deyou Zheng, Herbert M Lachman
BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing...
2017: Molecular Autism
https://www.readbyqxmd.com/read/28297715/autism-gene-ube3a-and-seizures-impair-sociability-by-repressing-vta-cbln1
#4
Vaishnav Krishnan, David C Stoppel, Yi Nong, Mark A Johnson, Monica J S Nadler, Ekim Ozkaynak, Brian L Teng, Ikue Nagakura, Fahim Mohammad, Michael A Silva, Sally Peterson, Tristan J Cruz, Ekkehard M Kasper, Ramy Arnaout, Matthew P Anderson
Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A...
March 23, 2017: Nature
https://www.readbyqxmd.com/read/28289282/the-schizophrenia-and-autism-associated-gene-transcription-factor-4-regulates-the-columnar-distribution-of-layer-2-3-prefrontal-pyramidal-neurons-in-an-activity-dependent-manner
#5
S C Page, G R Hamersky, R A Gallo, M D Rannals, N E Calcaterra, M N Campbell, B Mayfield, A Briley, B N Phan, A E Jaffe, B J Maher
Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2...
March 14, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28284582/the-association-of-cntnap2-rs7794745-gene-polymorphism-and-autism-in-iranian-population
#6
Sahar Zare, Farhad Mashayekhi, Elham Bidabadi
Autism is a heterogeneous and multifactorial disease that results from the interaction between genetic vulnerability and environmental factors. Several studies showed that many of genes that play role in autism are component of signaling networks that regulate growth and synaptic plasticity, play an important role in the etiology of autism. Contactin associated-like 2 (CNTNAP2) gene is a member of the superfamily of synaptic adhesion proteins and encodes a scaffold protein called CASPR2 that is involved in the interaction of neuron-glia and clusters K(+) channels in myelinated axons...
March 8, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28262759/role-of-a-circadian-relevant-gene-nr1d1-in-brain-development-possible-involvement-in-the-pathophysiology-of-autism-spectrum-disorders
#7
Masahide Goto, Makoto Mizuno, Ayumi Matsumoto, Zhiliang Yang, Eriko F Jimbo, Hidenori Tabata, Takanori Yamagata, Koh-Ichi Nagata
In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c.1499 G > A (p.R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28192273/gabaa-receptor-subtypes-in-the-mouse-brain-regional-mapping-and-diazepam-receptor-occupancy-by-in-vivo-18-f-flumazenil-pet
#8
Adrienne Müller Herde, Dietmar Benke, William T Ralvenius, Linjing Mu, Roger Schibli, Hanns Ulrich Zeilhofer, Stefanie D Krämer
Classical benzodiazepines, which are widely used as sedatives, anxiolytics and anticonvulsants, exert their therapeutic effects through interactions with heteropentameric GABAA receptors composed of two α, two β and one γ2 subunit. Their high affinity binding site is located at the interface between the γ2 and the adjacent α subunit. The α-subunit gene family consists of six members and receptors can be homomeric or mixed with respect to the α-subunits. Previous work has suggested that benzodiazepine binding site ligands with selectivity for individual GABAA receptor subtypes, as defined by the benzodiazepine-binding α subunit, may have fewer side effects and may even be effective in diseases, such as schizophrenia, autism or chronic pain, that do not respond well to classical benzodiazepines...
February 10, 2017: NeuroImage
https://www.readbyqxmd.com/read/28191889/targeted-sequencing-identifies-91-neurodevelopmental-disorder-risk-genes-with-autism-and-developmental-disability-biases
#9
Holly A F Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt, Christopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G Amaral, Ingrid E Scheffer, Martin B Delatycki, Paul J Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A Bernier, Evan E Eichler
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100)...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28137726/molecular-analyses-of-neurogenic-defects-in-a-human-pluripotent-stem-cell-model-of-fragile-x-syndrome
#10
Michael J Boland, Kristopher L Nazor, Ha T Tran, Attila Szücs, Candace L Lynch, Ryder Paredes, Flora Tassone, Pietro Paolo Sanna, Randi J Hagerman, Jeanne F Loring
New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models...
January 29, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28130356/a-novel-human-camk2a-mutation-disrupts-dendritic-morphology-and-synaptic-transmission-and-causes-asd-related-behaviors
#11
Jason R Stephenson, Xiaohan Wang, Tyler L Perfitt, Walker P Parrish, Brian C Shonesy, Christian R Marks, Douglas P Mortlock, Terunaga Nakagawa, James S Sutcliffe, Roger J Colbran
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation...
February 22, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28118382/integrative-variation-analysis-reveals-that-a-complex-genotype-may-specify-phenotype-in-siblings-with-syndromic-autism-spectrum-disorder
#12
Viviane Neri de Souza Reis, João Paulo Kitajima, Ana Carolina Tahira, Ana Cecília Feio-Dos-Santos, Rodrigo Ambrósio Fock, Bianca Cristina Garcia Lisboa, Sérgio Nery Simões, Ana C V Krepischi, Carla Rosenberg, Naila Cristina Lourenço, Maria Rita Passos-Bueno, Helena Brentani
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations-single nucleotide variants (SNVs) or small insertions and deletions (indels)-with probable functional impacts...
2017: PloS One
https://www.readbyqxmd.com/read/28032018/a-multi-target-small-molecule-for-targeted-transcriptional-activation-of-therapeutically-significant-nervous-system-genes
#13
Yulei Wei, Ganesh N Pandian, Tingting Zou, Junichi Taniguchi, Shinsuke Sato, Gengo Kashiwazaki, Thangavel Vaijayanthi, Takuya Hidaka, Toshikazu Bando, Hiroshi Sugiyama
An integrated multi-target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell-fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence-specific DNA binding pyrrole-imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA-based epigenetic ON switch termed SAHA-L as the first-ever multi-target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7-iPS cells...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/28017919/relationship-of-a-common-oxtr-gene-variant-to-brain-structure-and-default-mode-network-function-in-healthy-humans
#14
Junping Wang, Meredith N Braskie, George W Hafzalla, Joshua Faskowitz, Katie L McMahon, Greig I de Zubicaray, Margaret J Wright, Chunshui Yu, Paul M Thompson
A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity)...
February 15, 2017: NeuroImage
https://www.readbyqxmd.com/read/28000768/knowledge-guided-bioinformatics-model-for-identifying-autism-spectrum-disorder-diagnostic-microrna-biomarkers
#15
Li Shen, Yuxin Lin, Zhandong Sun, Xuye Yuan, Luonan Chen, Bairong Shen
Autism spectrum disorder (ASD) is a severe neurodevelopmental disease with a high incidence and effective biomarkers are urgently needed for its diagnosis. A few previous studies have reported the detection of miRNA biomarkers for autism diagnosis, especially those based on bioinformatics approaches. In this study, we developed a knowledge-guided bioinformatics model for identifying autism miRNA biomarkers. We downloaded gene expression microarray data from the GEO Database and extracted genes with expression levels that differed in ASD and the controls...
December 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27983596/estrogenic-endocrine-disrupting-chemicals-influencing-nrf1-regulated-gene-networks-in-the-development-of-complex-human-brain-diseases
#16
REVIEW
Mark Preciados, Changwon Yoo, Deodutta Roy
During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese...
December 13, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27932026/gene-environment-interactions-in-cortical-interneuron-development-and-dysfunction-a-review-of-preclinical-studies
#17
REVIEW
Lydia J Ansen-Wilson, Robert J Lipinski
Cortical interneurons (cINs) are a diverse group of locally projecting neurons essential to the organization and regulation of neural networks. Though they comprise only ∼20% of neurons in the neocortex, their dynamic modulation of cortical activity is requisite for normal cognition and underlies multiple aspects of learning and memory. While displaying significant morphological, molecular, and electrophysiological variability, cINs collectively function to maintain the excitatory-inhibitory balance in the cortex by dampening hyperexcitability and synchronizing activity of projection neurons, primarily through use of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)...
January 2017: Neurotoxicology
https://www.readbyqxmd.com/read/27919067/genome-wide-changes-in-lncrna-splicing-and-regional-gene-expression-patterns-in-autism
#18
Neelroop N Parikshak, Vivek Swarup, T Grant Belgard, Manuel Irimia, Gokul Ramaswami, Michael J Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer K Lowe, Benjamin J Blencowe, Steve Horvath, Daniel H Geschwind
Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes...
December 15, 2016: Nature
https://www.readbyqxmd.com/read/27897003/de-novo-mutations-in-autism-implicate-the-synaptic-elimination-network
#19
Guhan Ram Venkataraman, Chloe O'Connell, Fumiko Egawa, Dorna Kashef-Haghighi, Dennis P Wall
Autism has been shown to have a major genetic risk component; the architecture of documented autism in families has been over and again shown to be passed down for generations. While inherited risk plays an important role in the autistic nature of children, de novo (germline) mutations have also been implicated in autism risk. Here we find that autism de novo variants verified and published in the literature are Bonferroni-significantly enriched in a gene set implicated in synaptic elimination. Additionally, several of the genes in this synaptic elimination set that were enriched in protein-protein interactions (CACNA1C, SHANK2, SYNGAP1, NLGN3, NRXN1, and PTEN) have been previously confirmed as genes that confer risk for the disorder...
2016: Pacific Symposium on Biocomputing
https://www.readbyqxmd.com/read/27893730/fluorescent-nanodiamond-tracking-reveals-intraneuronal-transport-abnormalities-induced-by-brain-disease-related-genetic-risk-factors
#20
Simon Haziza, Nitin Mohan, Yann Loe-Mie, Aude-Marie Lepagnol-Bestel, Sophie Massou, Marie-Pierre Adam, Xuan Loc Le, Julia Viard, Christine Plancon, Rachel Daudin, Pascale Koebel, Emilie Dorard, Christiane Rose, Feng-Jen Hsieh, Chih-Che Wu, Brigitte Potier, Yann Herault, Carlo Sala, Aiden Corvin, Bernadette Allinquant, Huan-Cheng Chang, François Treussart, Michel Simonneau
Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs)...
November 28, 2016: Nature Nanotechnology
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