Mouse Nlgn3 Knockout Project (CRISPR/Cas9)
Total Page：16
File Type：pdf, Size：1020Kb
Load more
Recommended publications
-
Screening of a Clinically and Biochemically Diagnosed SOD Patient Using Exome Sequencing: a Case Report with a Mutations/Variations Analysis Approach
The Egyptian Journal of Medical Human Genetics (2016) 17, 131–136 HOSTED BY Ain Shams University The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net www.sciencedirect.com CASE REPORT Screening of a clinically and biochemically diagnosed SOD patient using exome sequencing: A case report with a mutations/variations analysis approach Mohamad-Reza Aghanoori a,b,1, Ghazaleh Mohammadzadeh Shahriary c,2, Mahdi Safarpour d,3, Ahmad Ebrahimi d,* a Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran b Research and Development Division, RoyaBioGene Co., Tehran, Iran c Department of Genetics, Shahid Chamran University of Ahvaz, Ahvaz, Iran d Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Received 12 May 2015; accepted 15 June 2015 Available online 22 July 2015 KEYWORDS Abstract Background: Sulfite oxidase deficiency (SOD) is a rare neurometabolic inherited disor- Sulfite oxidase deficiency; der causing severe delay in developmental stages and premature death. The disease follows an auto- Case report; somal recessive pattern of inheritance and causes deficiency in the activity of sulfite oxidase, an Exome sequencing enzyme that normally catalyzes conversion of sulfite to sulfate. Aim of the study: SOD is an underdiagnosed disorder and its diagnosis can be difficult in young infants as early clinical features and neuroimaging changes may imitate some common diseases. Since the prognosis of the disease is poor, using exome sequencing as a powerful and efficient strat- egy for identifying the genes underlying rare mendelian disorders can provide important knowledge about early diagnosis, disease mechanisms, biological pathways, and potential therapeutic targets. -
Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies
International Journal of Environmental Research and Public Health Review Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies Noor B. Almandil 1,† , Deem N. Alkuroud 2,†, Sayed AbdulAzeez 2, Abdulla AlSulaiman 3, Abdelhamid Elaissari 4 and J. Francis Borgio 2,* 1 Department of Clinical Pharmacy Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] 2 Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] (D.N.A.); [email protected] (S.A.) 3 Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] or [email protected] 4 Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, F-69622 Lyon, France; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +966-13-333-0864 † These authors contributed equally to this work. Received: 26 January 2019; Accepted: 19 February 2019; Published: 23 February 2019 Abstract: One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. -
Excess of Rare Novel Loss-Of-Function Variants in Synaptic Genes in Schizophrenia and Autism Spectrum Disorders
Molecular Psychiatry (2014) 19, 872–879 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders EM Kenny1,3, P Cormican1,3, S Furlong1,3, E Heron1, G Kenny1, C Fahey1, E Kelleher1, S Ennis2, D Tropea1, R Anney1, AP Corvin1, G Donohoe1, L Gallagher1, M Gill1 and DW Morris1 Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P ¼ 0.02). This effect was stronger when analysis was limited to singleton LoF variants (P ¼ 0.0007) and the excess was present in both SZ (P ¼ 0.002) and ASD (P ¼ 0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P ¼ 0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. -
Sequence and Functional Analysis of Schistosoma
MINING FOR CONSERVED MOTIFS AND SIGNIFICANT FUNCTIONS IN S. MANSONI CERCARIAL SECRETIONS Amy L. Schmidbauer Submitted to the faculty of the School of Informatics in partial fulfillment of the requirements for the degree Master of Science in Bioinformatics, Indiana University December 30, 2006 ii Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Master of Science in Bioinformatics. (Committee Chair’s signature)_______________________ Sean D. Mooney, Ph.D., Chair Master’s Thesis Committee (Second member’s signature)________________________ Xiaoman Shawn Li, Ph.D. (Third member’s signature)__________ _______________ William J. Sullivan, Ph.D. ii © 2006 Amy L. Schmidbauer All Rights Reserved iii ACKNOWLEDGMENTS This project would not have been possible without the guidance and support of many people including faculty, advisors, colleagues, friends and family. I am extremely grateful to my advisor, Dr. Sean Mooney, for welcoming me into his laboratory as a graduate student, and for providing, not only computing resources, but continued support, suggestions, and guidance as, what started out as an independent study project, grew into what became this thesis. I extend my sincere appreciation to Dr. Giselle Knudsen, an honorary member of my thesis committee, for the original project inspiration, for her enthusiastic encouragement, insight, and direction throughout the project, and for her thoughtful review of this thesis. I would like also like to extend a heartfelt thank you to Dr. William Sullivan and Dr. Xiaoman Li for their willingness to lend their time to reviewing my thesis and for the insightful feedback they provided. For statistical expertise and support I would like to extend my deepest appreciation to Dr. -
Neuroligin3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.22.915801; this version posted January 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Accelerated Communication Title Neuroligin3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function Running Title Nlgn3 expression and function in mouse hippocampal neurons Motokazu Uchigashima1,2,5, Ming Leung3,5, Takuya Watanabe1,5, Amy Cheung1, Masahiko Watanabe2, Yuka Imamura Kawasawa3,4 and Kensuke Futai1* 1Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, LRB-706 Worcester, MA 01605-2324, USA 2Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan 3Department of Biochemistry and Molecular Biology and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA 4Department of Pharmacology Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA 5These authors contributed equally *Corresponding author: [email protected] Tel: 1-774-455-4318 KEYWORDS Neuron, trans-synaptic cell adhesion, excitatory and inhibitory balance, hippocampus bioRxiv preprint doi: https://doi.org/10.1101/2020.01.22.915801; this version posted January 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Synapse formation is a dynamic process essential for neuronal circuit development and maturation. At the synaptic cleft, trans-synaptic protein-protein interactions constitute major biological determinants of proper synapse efficacy. -
Advances in Autism Genetics: on the Threshold of a New Neurobiology
REVIEWS Advances in autism genetics: on the threshold of a new neurobiology Brett S. Abrahams and Daniel H. Geschwind Abstract | Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme. Gene association studies Autistic disorder is the most severe end of a group of into the ASDs. This work, in concert with important A set of methods that is used neurodevelopmental disorders referred to as autism technical advances, made it possible to carry out the to determine the correlation spectrum disorders (ASDs), all of which share the com- first candidate gene association studies and resequenc- (positive or negative) between mon feature of dysfunctional reciprocal social interac- ing efforts in the late 1990s. Whole-genome linkage a defined genetic variant and a studies phenotype of interest. tion. A meta-analysis of ASD prevalence rates suggests followed, and were used to identify additional that approximately 37 in 10,000 individuals are affected1. loci of potential interest. Although -
Mirna Regulons Associated with Synaptic Function
miRNA Regulons Associated with Synaptic Function Maria Paschou1, Maria D. Paraskevopoulou2, Ioannis S. Vlachos2, Pelagia Koukouraki1, Artemis G. Hatzigeorgiou2,3, Epaminondas Doxakis1* 1 Basic Neurosciences Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece, 2 Institute of Molecular Oncology, Biomedical Sciences Research Center ‘‘Alexander Fleming’’ Vari, Greece, 3 Department of Computer and Communication Engineering, University of Thessaly, Volos, Greece Abstract Differential RNA localization and local protein synthesis regulate synapse function and plasticity in neurons. MicroRNAs are a conserved class of regulatory RNAs that control mRNA stability and translation in tissues. They are abundant in the brain but the extent into which they are involved in synaptic mRNA regulation is poorly known. Herein, a computational analysis of the coding and 39UTR regions of 242 presynaptic and 304 postsynaptic proteins revealed that 91% of them are predicted to be microRNA targets. Analysis of the longest 39UTR isoform of synaptic transcripts showed that presynaptic mRNAs have significantly longer 39UTR than control and postsynaptic mRNAs. In contrast, the shortest 39UTR isoform of postsynaptic mRNAs is significantly shorter than control and presynaptic mRNAs, indicating they avert microRNA regulation under specific conditions. Examination of microRNA binding site density of synaptic 39UTRs revealed that they are twice as dense as the rest of protein-coding transcripts and that approximately 50% of synaptic transcripts are predicted to have more than five different microRNA sites. An interaction map exploring the association of microRNAs and their targets revealed that a small set of ten microRNAs is predicted to regulate 77% and 80% of presynaptic and postsynaptic transcripts, respectively. -
No Evidence for Involvement of Genetic Variants in the X-Linked
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:535–537 (2008) Brief Research Communication No Evidence for Involvement of Genetic Variants in the X-Linked Neuroligin Genes NLGN3 and NLGN4X in Probands With Autism Spectrum Disorder on High Functioning Level Anne-Kathrin Wermter,1* Inge Kamp-Becker,2 Konstantin Strauch,3 Gerd Schulte-Ko¨ rne,2 and Helmut Remschmidt2 1Clinical Research Group, Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University of Marburg, Marburg, Germany 2Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University of Marburg, Marburg, Germany 3Institute of Medical Biometry and Epidemiology, Philipps University of Marburg, Marburg, Germany Several lines of evidence indicate a role of in the X-Linked Neuroligin Genes NLGN3 and NLGN4X mutations in the two X-linked genes neuroligin in Probands With Autism Spectrum Disorder on High 3(NLGN3) and neuroligin 4 (NLGN4X) in the Functioning Level. Am J Med Genet Part B 147B:535–537. etiology of autistic spectrum disorders. To ana- lyze whether genetic variants in the NLGN3 and NLGN4X genes occurs in patients with autistic Autism spectrum disorders (ASD) are a family of neuro- disorders on high functioning level, we perform- developmental disorders characterized by early-onset delays ed a mutation screen of both genes using SSCP and deviance in the development of social, communicative in 107 probands with Asperger syndrome, high- skills and restricted, stereotyped pattern of interests and functioning autism and atypical autism. We iden- activities [Volkmar et al., 2004]. Despite the fact that there are tified four polymorphisms (rs2290488, rs7049300, many similarities within the spectrum of autistic disorders rs3747333, rs3747334) and one novel synonymous the condition is characterized by great variability of clinical variant (A558) in the NLGN4X. -
Mutations in Neuroligin-3 in Male Mice Impact Behavioral Flexibility but Not Relational Memory in a Touchscreen Test of Visual Transitive Inference Rebecca H
Norris et al. Molecular Autism (2019) 10:42 https://doi.org/10.1186/s13229-019-0292-2 RESEARCH Open Access Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference Rebecca H. C. Norris1, Leonid Churilov2,3, Anthony J. Hannan1,4,5 and Jess Nithianantharajah1,4* Abstract Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms. -
With Autism Spectrum Disorders in a Chinese Han Cohort Jindan Yu1, Xue He1, Dan Yao1, Zhongyue Li2, Hui Li3 and Zhengyan Zhao1*
Yu et al. Behavioral and Brain Functions 2011, 7:13 http://www.behavioralandbrainfunctions.com/content/7/1/13 RESEARCH Open Access A sex-specific association of common variants of neuroligin genes (NLGN3 and NLGN4X) with autism spectrum disorders in a Chinese Han cohort Jindan Yu1, Xue He1, Dan Yao1, Zhongyue Li2, Hui Li3 and Zhengyan Zhao1* Abstract Background: Synaptic genes, NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs. But no such rare variant in these two genes has as yet been adequately replicated in Chinese population and no common variant has been further investigated to be associated with ASDs. Methods: 7 known ASDs-related rare variants in NLGN3 and NLGN4X genes were screened for replication of the initial findings and 12 intronic tagging single nucleotide polymorphisms (SNPs) were genotyped for case-control association analysis in a total of 229 ASDs cases and 184 control individuals in a Chinese Han cohort, using matrix- assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: We found that a common intronic variant, SNP rs4844285 in NLGN3 gene, and a specific 3-marker haplotype XA-XG-XT (rs11795613-rs4844285-rs4844286) containing this individual SNP were associated with ASDs and showed a male bias, even after correction for multiple testing (SNP allele: P = 0.048, haplotype:P = 0.032). Simultaneously, none of these 7 known rare mutation of NLGN3 and NLGN4X genes was identified, neither in our patients with ASDs nor controls, giving further evidence that these known rare variants might be not enriched in Chinese Han cohort. -
Dimerization of Postsynaptic Neuroligin Drives Synaptic Assembly Via Transsynaptic Clustering of Neurexin
Dimerization of postsynaptic neuroligin drives synaptic assembly via transsynaptic clustering of neurexin Seth L. Shipmana,b and Roger A. Nicolla,1 aDepartment of Cellular and Molecular Pharmacology and Physiology and bNeuroscience Graduate Program, University of California, San Francisco, CA 94158 Contributed by Roger A. Nicoll, October 9, 2012 (sent for review May 5, 2012) The transsynaptic complex of neuroligin (NLGN) and neurexin forms Like the synapse, the neuroligin/neurexin complex is itself asym- a physical connection between pre- and postsynaptic neurons that metric. Neuroligin exists natively as a dimer, whereas neurexin, in an occurs early in the course of new synapse assembly. Both neuroligin unbound state, is monomeric (10). The complex, then, is an asym- and neurexin have, indeed, been proposed to exhibit active, in- metric tetramer consisting of a neuroligin dimer and two neurexin structive roles in the formation of synapses. However, the process by molecules—the neurexin molecules brought in close proximity to which these instructive roles play out during synaptogenesis is not each other via their interaction with the neuroligin dimer (10–12). well understood. Here, we examine one aspect of postsynaptic As stated above, in vitro evidence suggests that neurexin clustering neuroligin with regard to its synaptogenic properties: its basal state may be an early step in the differentiation of an axon segment into as a constitutive dimer. We show that dimerization is required for a presynaptic terminal (13). Such clustering could be achieved by the the synaptogenic properties of neuroligin and likely serves to induce monomeric-to-dimeric conversion of neurexin upon neuroligin presynaptic differentiation via a transsynaptic clustering of neu- binding. -
ABSTRACT SHU, XIAOMEI. Pathogenesis and Host Response
ABSTRACT SHU, XIAOMEI. Pathogenesis and Host Response During Infection of Maize Kernels by Aspergillus flavus and Fusarium verticillioides. (Under the direction of Dr. Gary A. Payne.) Developing maize kernels are vulnerable to colonization by microbes. When colonization allows proliferation of the microbe at the expense of the host, disease occurs. The ascomycete fungal pathogens Aspergillus flavus and Fusarium verticillioides are capable of colonizing maize kernels, causing ear rots and contamination of the kernel with mycotoxins. These diseases lead to significant losses of crop yield and quality, and constitute a threat to food safety and human health. Thus, the significance of these diseases has prompted extensive research efforts to understand these plant-parasite interactions. However, pathogenesis and resistance mechanisms remain poorly characterized, hampering the development of effective control strategies. No commercial maize lines are completely resistant to these fungi. We applied an integrated approach consisting of histology, in situ gene expression and transcriptional profiling to better understand the nature of the interactions that occur between maize kernels and these fungi. Maize inbred line B73 was hand pollinated and inoculated with either A. flavus or F. verticillioides by wounding the kernel with a needle bearing conidia. Histological staining of the kernel sections revealed fungal mycelium in kernels adjacent to the inoculation site by 48 hours post inoculation (hpi), and in all tissues at 96 hpi. Compared with F. verticillioides, A. flavus more aggressively colonized kernel tissue and formed a unique biofilm-like structure around the scutellum. Transcriptome profiling using RNA-sequencing (RNA-seq) coupled with pathway analysis showed that these fungi were recognized by the kernel tissues prior to visible colonization.