DOCSLIB.ORG

Download The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Download The REGULATION OF DENDRITIC MORPHOLOGY AND SYNAPSE FORMATION BY THE INTELLECTUAL DISABILITY ASSOCIATED PALMITOYL ACYL TRANSFERASES zDHHC15 and zDHHC9 by Jordan J. Shimell B.Sc., B.A., Simon Fraser University, 2011 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Neuroscience) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 © Jordan J. Shimell, 2019 The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Regulation of dendritic morphology and synapse formation by the intellectual disability associated palmitoyl acyl transferases zDHHC15 and zDHHC9 submitted by Jordan J. Shimell in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience Examining Committee: Shernaz Bamji, Cellular and Physiological Sciences Supervisor Elizabeth Conibear, Biochemistry Supervisory Committee Member Calvin Roskelly, Cellular and Physiological Sciences University Examiner Stefan Taubert, Medical Genetics University Examiner Additional Supervisory Committee Members: Tim O’Connor, Cellular and Physiological Sciences Supervisory Committee Member Lynn Raymond, Psychiatry Supervisory Committee Member ii Abstract Palmitoylation is a reversible post-translational modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by a family of palmitoyl acyltransferases known as zDHHC enzymes and mounting evidence suggests that these enzymes play key roles in the development and function of neuronal connections. Additionally, a number of zDHHCs have been associated with neurodevelopmental, neurological and neurodegenerative diseases. Loss-of-function variants in zDHHC15 and zDHHC9 are associated with intellectual disabilities; however, there is limited information on the function of these enzymes in the brain. This dissertation discusses work that demonstrates that zDHHC15 and zDHHC9 palmitoylation independently regulate dendritic arborization and are required for the formation and/or maintenance of excitatory (zDHHC15) and inhibitory (zDHHC9) synapses, thereby regulating the balance between excitation and inhibition. Loss of zDHHC15 function inhibits dendrite growth and decreases the palmitoylation and trafficking of PSD-95 into dendrites, leading to deficits in spine maturation. Loss of zDHHC9 function promotes dendritic retraction through aberrant palmitoylation of the small GTPase, Ras, and decreases the formation/maintenance of inhibitory synapses by decreasing the palmitoylation of the small GTPase, TC10. As well, knocking out zDHHC9 in mice results in decreased palmitoylation of Ras and TC10, and leads to elevated synaptic excitability and seizure-like activity. This work provides new insights into the function of zDHHC15 and zDHHC9 and provides a plausible mechanism for how loss-of-function mutations in these proteins may contribute to the etiology of intellectual disability. iii Lay Summary Neurons are specialized nervous system cells with elongated processes called axons and dendrites. When axons from one neuron make contact with dendrites from another neuron, specialized junctions (synapses) are formed, which allow communication between neurons. Dysfunction in dendrites and/or synapses are thought to underlie brain disorders, including intellectual disabilities. Neurons must transport proteins over long distances within dendrites and axons, which requires reliable transport mechanisms. One method to achieve this is the addition of a fatty acid, a process known as “palmitoylation”, which plays a central role in dendrite and synapse function. Indeed, approximately 41% of all synaptic proteins can be palmitoylated. Mutations in two enzymes that regulate palmitoylation, zDHHC15 and zDHHC9, have been identified in patients with intellectual disability. In this dissertation, I determine that these enzymes are critical for dendrite growth and synapse formation, and provide a mechanism for how loss of these enzymes contributes to intellectual disability. iv Preface The work in Chapter 2, entitled “Regulation of Dendrite Morphology and Excitatory Synapse Formation by zDHHC15” has been published as: Shah, B.S.1, Shimell, J.J.1, & Bamji, S.X. Regulation of dendrite morphology and excitatory synapse formation by zDHHC15. Journal of Cell Science, doi:10.1242/jcs.230052. 1These authors contributed equally to this work. All experiments were conceived by BSS, JJS, and SXB, and all experiments were jointly conducted by BSS and JJS. Experiments by BSS and JJS were done in equal partnership with equal intellectual contribution. Bhavin Shah performed the developmental time course Western blots, localization immunochemistry, biotinylation assays, dendritic imaging, spine analysis, and synaptic imaging. Jordan Shimell performed colocalization experiments with PSD- 95, gephyrin, and giantin, Western blots for protein expression, live imaging of dendritic growth dynamics, palmitoylation assays, and fluorescence recovery after photobleaching (FRAP) experiments. Jordan Shimell and Bhavin Shah performed all analysis, data curation, figure creation, and manuscript preparation equally. The work in Chapter 3, entitled “The X-linked Intellectual Disability Gene, zDHHC9, is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation” is accepted in principle and will be published in Cell Reports as: Shimell, J.J., Shah, B.S., Cain, S.M., Thouta, S., Jovellar, D.B., Brigidi, G.S., Kass, J., Tatarnikov, I., Kuhlmann, N., Milnerwood, A., Snutch, T.P. & Bamji, S.X. The X-linked intellectual disability gene, zDHHC9, is essential for dendrite outgrowth and inhibitory synapse formation. (accepted in principle at Cell Reports). Experiments were conceived by JJS, GSB, BSS and SXB, and conducted by JJS with the following exceptions: DBJ assisted with immunos and imaging for colocalization and imaging and quantification for synapse density. BSS helped perform palmitoylation assays for TC10 in HEK Cells. SMC, ST, JK, and TPC designed and performed the in vivo electrophysiology experiments. IT, NK, and AM designed and performed in vitro electrophysiological experiments. v JJS and SXB wrote the manuscript with contribution for electrophysiology sections from SMC, ST, and TPC. Ethics Certificate Numbers: The animal studies presented in this dissertation were performed with ethical approval from the UBC Animal Care Committee (certificates #A15-0081, #A14-0338, #A18-0331, #A16-0288, and #A19-0137). vi Table of Contents Abstract ...........................................................................................................................................3 Lay Summary .................................................................................................................................4 Preface .............................................................................................................................................5 Table of Contents ...........................................................................................................................7 List of Tables ................................................................................................................................13 List of Figures ...............................................................................................................................14 List of Abbreviations ...................................................................................................................17 Acknowledgements ......................................................................................................................20 Chapter 1: Introduction ................................................................................................................1 1.1 The Hippocampus as a Model System ............................................................................ 1 1.2 Post-Translational Modification of Proteins: Lipidation ................................................ 4 1.3 Protein Palmitoylation .................................................................................................... 5 1.3.1 Palmitoylation Enzymes ............................................................................................. 7 1.3.2 Quantitative Assessment of Protein Palmitoylation ................................................. 10 1.3.3 Functional Consequences of Palmitoylation ............................................................. 13 1.4 Palmitoylation in the Nervous System .......................................................................... 14 1.4.1 Involvement of Palmitoylation in Neurodevelopmental and Neurological Disease and Disorder .......................................................................................................................... 15 1.5 Intellectual Disability .................................................................................................... 15 1.6 zDHHC15 ..................................................................................................................... 17 1.7 zDHHC9 ....................................................................................................................... 18 1.8 zDHHC15 and zDHHC9 in Neuronal Connectivity ..................................................... 20 vii 1.9 Dendrite Development .................................................................................................
Load more

Recommended publications
  • Identification of Key Genes and Pathways in Pancreatic Cancer
    G C A T T A C G G C A T genes Article Identification of Key Genes and Pathways in Pancreatic Cancer Gene Expression Profile by Integrative Analysis Wenzong Lu * , Ning Li and Fuyuan Liao Department of Biomedical Engineering, College of Electronic and Information Engineering, Xi’an Technological University, Xi’an 710021, China * Correspondence: [email protected]; Tel.: +86-29-86173358 Received: 6 July 2019; Accepted: 7 August 2019; Published: 13 August 2019 Abstract: Background: Pancreatic cancer is one of the malignant tumors that threaten human health. Methods: The gene expression profiles of GSE15471, GSE19650, GSE32676 and GSE71989 were downloaded from the gene expression omnibus database including pancreatic cancer and normal samples. The differentially expressed genes between the two types of samples were identified with the Limma package using R language. The gene ontology functional and pathway enrichment analyses of differentially-expressed genes were performed by the DAVID software followed by the construction of a protein–protein interaction network. Hub gene identification was performed by the plug-in cytoHubba in cytoscape software, and the reliability and survival analysis of hub genes was carried out in The Cancer Genome Atlas gene expression data. Results: The 138 differentially expressed genes were significantly enriched in biological processes including cell migration, cell adhesion and several pathways, mainly associated with extracellular matrix-receptor interaction and focal adhesion pathway in pancreatic cancer. The top hub genes, namely thrombospondin 1, DNA topoisomerase II alpha, syndecan 1, maternal embryonic leucine zipper kinase and proto-oncogene receptor tyrosine kinase Met were identified from the protein–protein interaction network.
    [Show full text]
  • Meta-Analysis of Gene Expression in Individuals with Autism Spectrum Disorders
    Meta-analysis of Gene Expression in Individuals with Autism Spectrum Disorders by Carolyn Lin Wei Ch’ng BSc., University of Michigan Ann Arbor, 2011 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Bioinformatics) The University of British Columbia (Vancouver) August 2013 c Carolyn Lin Wei Ch’ng, 2013 Abstract Autism spectrum disorders (ASD) are clinically heterogeneous and biologically complex. State of the art genetics research has unveiled a large number of variants linked to ASD. But in general it remains unclear, what biological factors lead to changes in the brains of autistic individuals. We build on the premise that these heterogeneous genetic or genomic aberra- tions will converge towards a common impact downstream, which might be reflected in the transcriptomes of individuals with ASD. Similarly, a considerable number of transcriptome analyses have been performed in attempts to address this question, but their findings lack a clear consensus. As a result, each of these individual studies has not led to any significant advance in understanding the autistic phenotype as a whole. The goal of this research is to comprehensively re-evaluate these expression profiling studies by conducting a systematic meta-analysis. Here, we report a meta-analysis of over 1000 microarrays across twelve independent studies on expression changes in ASD compared to unaffected individuals, in blood and brain. We identified a number of genes that are consistently differentially expressed across studies of the brain, suggestive of effects on mitochondrial function. In blood, consistent changes were more difficult to identify, despite individual studies tending to exhibit larger effects than the brain studies.
    [Show full text]
  • Disruption of the Zdhhc9 Intellectual Disability Gene Leads to Behavioural T Abnormalities in a Mouse Model
    Experimental Neurology 308 (2018) 35–46 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Research Paper Disruption of the Zdhhc9 intellectual disability gene leads to behavioural T abnormalities in a mouse model Marianna Kouskou, David M. Thomson, Ros R. Brett, Lee Wheeler, Rothwelle J. Tate, ⁎ Judith A. Pratt, Luke H. Chamberlain Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom ARTICLE INFO ABSTRACT Keywords: Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of zDHHC enzymes a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that zDHHC9 exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause Intellectual disability mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus H-Ras callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phe- S-acylation notyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of Palmitoylation disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI.
    [Show full text]
  • Expanding the Clinical Phenotype of Patients with a ZDHHC9 Mutation Alice Masurel-Paulet,1 Vera M
    CLINICAL REPORT Expanding the Clinical Phenotype of Patients With a ZDHHC9 Mutation Alice Masurel-Paulet,1 Vera M. Kalscheuer,2 Nicolas Lebrun,3 Hao Hu,2 Fabienne Levy,4 Christel Thauvin-Robinet,1,5 Ve´ronique Darmency-Stamboul,4,6 Salima El Chehadeh,1 Julien Thevenon,1,5 Sophie Chancenotte,4 Marie Ruffier-Bourdet,4 Marle`ne Bonnet,4 Jean-Michel Pinoit,7 Fre´de´ric Huet,6 Vincent Desportes,8 Jamel Chelly,3 and Laurence Faivre1,5* 1Centre de Ge´ne´tique et Centre de Re´fe´rence Anomalies du de´veloppement et Syndromes Malformatifs, Hoˆpital d’Enfants, CHU, Dijon, France 2Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany 3Inserm U1016, Institut Cochin, Universite´ Paris-Descartes, CNRS (UMR 8104), Paris, France 4Centre Re´fe´rent des Troubles du Langage et des Apprentissages, Hoˆpital d’Enfants, CHU, Dijon, France 5EA 4271 GAD, Faculte´ de Me´decine, Universite´ de Bourgogne, Dijon, France 6Service de Pe´diatrie 1, Hoˆpital d’Enfants, CHU, Dijon, France 7Service de Pe´dopsychiatrie, Hoˆpital d’Enfants, CHU, Dijon, France 8Service de Neurologie Pe´diatrique, CHU Lyon, Hoˆpital Femme Me`re Enfant, Bron, France Manuscript Received: 19 April 2013; Manuscript Accepted: 9 October 2013 In 2007, 250 families with X-linked intellectual disability (XLID) were screened for mutations in genes on the X-chromosome, and How to Cite this Article: ZDHHC9 in 4 of these families, mutations in the gene were Masurel-Paulet A, Kalscheuer VM, Lebrun identified. The ID was either isolated or associated with a N, Hu H, Levy F, Thauvin-Robinet C, marfanoid habitus.
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • Statistical and Bioinformatic Analysis of Hemimethylation Patterns in Non-Small Cell Lung Cancer Shuying Sun1* , Austin Zane2, Carolyn Fulton3 and Jasmine Philipoom4
    Sun et al. BMC Cancer (2021) 21:268 https://doi.org/10.1186/s12885-021-07990-7 RESEARCH ARTICLE Open Access Statistical and bioinformatic analysis of hemimethylation patterns in non-small cell lung cancer Shuying Sun1* , Austin Zane2, Carolyn Fulton3 and Jasmine Philipoom4 Abstract Background: DNA methylation is an epigenetic event involving the addition of a methyl-group to a cytosine- guanine base pair (i.e., CpG site). It is associated with different cancers. Our research focuses on studying non-small cell lung cancer hemimethylation, which refers to methylation occurring on only one of the two DNA strands. Many studies often assume that methylation occurs on both DNA strands at a CpG site. However, recent publications show the existence of hemimethylation and its significant impact. Therefore, it is important to identify cancer hemimethylation patterns. Methods: In this paper, we use the Wilcoxon signed rank test to identify hemimethylated CpG sites based on publicly available non-small cell lung cancer methylation sequencing data. We then identify two types of hemimethylated CpG clusters, regular and polarity clusters, and genes with large numbers of hemimethylated sites. Highly hemimethylated genes are then studied for their biological interactions using available bioinformatics tools. Results: In this paper, we have conducted the first-ever investigation of hemimethylation in lung cancer. Our results show that hemimethylation does exist in lung cells either as singletons or clusters. Most clusters contain only two or three CpG sites. Polarity clusters are much shorter than regular clusters and appear less frequently. The majority of clusters found in tumor samples have no overlap with clusters found in normal samples, and vice versa.
    [Show full text]
  • Statistical and Bioinformatic Analysis of Hemimethylation Patterns in Lung Cancer
    Statistical and Bioinformatic Analysis of Hemimethylation Patterns in Lung Cancer Shuying Sun ( [email protected] ) Texas State University San Marcos https://orcid.org/0000-0003-3974-6996 Austin Zane Texas A&M University College Station Carolyn Fulton Schreiner University Jasmine Philipoom Case Western Reserve University Research article Keywords: Methylation, Hemimethylation, Lung Cancer, Bioinformatics, Epigenetics Posted Date: March 20th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-17794/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on March 12th, 2021. See the published version at https://doi.org/10.1186/s12885-021-07990-7. Page 1/28 Abstract Background: DNA methylation is an epigenetic event involving the addition of a methyl-group to a cytosine-guanine base pair (i.e., CpG site). It is associated with different cancers. Our research focuses on studying lung cancer hemimethylation, which refers to methylation occurring on only one of the two DNA strands. Many studies often assume that methylation occurs on both DNA strands at a CpG site. However, recent publications show the existence of hemimethylation and its impact. It is important to identify cancer hemimethylation patterns. Methods: In this paper, we use the Wilcoxon signed rank test to identify hemimethylated CpG sites based on publicly available lung cancer methylation sequencing data. We then identify two types of hemimethylated CpG clusters, regular and polarity clusters, and genes with large numbers of hemimethylated sites. Highly hemimethylated genes are then studied for their biological interactions using available bioinformatics tools.
    [Show full text]
  • Role of Maternal Sin3a in Reprogramming Gene Expression During Mouse Preimplantation Development
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development Richard A. Jimenez University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Developmental Biology Commons, and the Genetics Commons Recommended Citation Jimenez, Richard A., "Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development" (2016). Publicly Accessible Penn Dissertations. 2366. https://repository.upenn.edu/edissertations/2366 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2366 For more information, please contact [email protected]. Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development Abstract In mouse, the maternal-to-zygotic transition entails a dramatic reprogramming of gene expression during the course of zygotic genome activation, which is essential for continued development beyond the 2-cell stage. Superimposed on zygotic genome activation and reprogramming of gene expression is formation of a chromatin-mediated transcriptionally repressive state that promotes repression of genes at the 2-cell stage. Experimentally inducing global histone hyperacetylation relieves this repression and histone deacetylase 1 (HDAC1) is the major HDAC involved in the development of this transcriptionally repressive state. Because SIN3A is essential
    [Show full text]
  • Sheet1 Page 1 Gene Symbol Gene Description Entrez Gene ID
    Sheet1 RefSeq ID ProbeSets Gene Symbol Gene Description Entrez Gene ID Sequence annotation Seed matches location(s) Ago-2 binding specific enrichment (replicate 1) Ago-2 binding specific enrichment (replicate 2) OE lysate log2 fold change (replicate 1) OE lysate log2 fold change (replicate 2) Probability NM_022823 218843_at FNDC4 Homo sapiens fibronectin type III domain containing 4 (FNDC4), mRNA. 64838 TR(1..1649)CDS(367..1071) 1523..1530 3.73 1.77 -1.91 -0.39 1 NM_003919 204688_at SGCE Homo sapiens sarcoglycan, epsilon (SGCE), transcript variant 2, mRNA. 8910 TR(1..1709)CDS(112..1425) 1495..1501 3.09 1.56 -1.02 -0.27 1 NM_006982 206837_at ALX1 Homo sapiens ALX homeobox 1 (ALX1), mRNA. 8092 TR(1..1320)CDS(5..985) 916..923 2.99 1.93 -0.19 -0.33 1 NM_019024 233642_s_at HEATR5B Homo sapiens HEAT repeat containing 5B (HEATR5B), mRNA. 54497 TR(1..6792)CDS(97..6312) 5827..5834,4309..4315 3.28 1.51 -0.92 -0.23 1 NM_018366 223431_at CNO Homo sapiens cappuccino homolog (mouse) (CNO), mRNA. 55330 TR(1..1546)CDS(96..749) 1062..1069,925..932 2.89 1.51 -1.2 -0.41 1 NM_032436 226194_at C13orf8 Homo sapiens chromosome 13 open reading frame 8 (C13orf8), mRNA. 283489 TR(1..3782)CDS(283..2721) 1756..1762,3587..3594,1725..1731,3395..3402 2.75 1.72 -1.38 -0.34 1 NM_031450 221534_at C11orf68 Homo sapiens chromosome 11 open reading frame 68 (C11orf68), mRNA. 83638 TR(1..1568)CDS(153..908) 967..973 3.07 1.35 -0.72 -0.06 1 NM_033318 225795_at,225794_s_at C22orf32 Homo sapiens chromosome 22 open reading frame 32 (C22orf32), mRNA.
    [Show full text]
  • Global and Local Connectivity Differences Converge with Gene Expression in a Neurodevelopmental Disorder of Known Genetic Origin
    bioRxiv preprint doi: https://doi.org/10.1101/057687; this version posted June 7, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Global and local connectivity differences converge with gene expression in a neurodevelopmental disorder of known genetic origin Joe Bathelt1, Jessica Barnes1, F Lucy Raymond2, Kate Baker1,2*, Duncan Astle1* 1 MRC Cognition & Brain Sciences Unit, Cambridge, UK 2 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom *these authors take joint responsibility for senior authorship 1 bioRxiv preprint doi: https://doi.org/10.1101/057687; this version posted June 7, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 Abstract Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment.
    [Show full text]
  • XLMR Genes: Update 2007
    European Journal of Human Genetics (2008) 16, 422–434 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg REVIEW XLMR genes: update 2007 Pietro Chiurazzi*,1, Charles E Schwartz2, Jozef Gecz3,4 and Giovanni Neri*,1 1Institute of Medical Genetics, Catholic University, Rome, Italy; 2JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC, USA; 3Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, South Australia, Australia; 4Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia X-linked mental retardation (XLMR) is a common cause of inherited intellectual disability with an estimated prevalence of B1/1000 males. Most XLMR conditions are inherited as X-linked recessive traits, although female carriers may manifest usually milder symptoms. We have listed 215 XLMR conditions, subdivided according to their clinical presentation: 149 with specific clinical findings, including 98 syndromes and 51 neuromuscular conditions, and 66 nonspecific (MRX) forms. We also present a map of the 82 XLMR genes cloned to date (November 2007) and a map of the 97 conditions that have been positioned by linkage analysis or cytogenetic breakpoints. We briefly consider the molecular function of known XLMR proteins and discuss the possible strategies to identify the remaining XLMR genes. Final remarks are made on the natural history of XLMR conditions and on diagnostic issues. European Journal of Human Genetics (2008) 16, 422–434; doi:10.1038/sj.ejhg.5201994;
    [Show full text]
  • A Computational Approach to Candidate Gene Prioritization for X
    Lombard et al. Biology Direct 2011, 6:30 http://www.biology-direct.com/content/6/1/30 RESEARCH Open Access A computational approach to candidate gene prioritization for X-linked mental retardation using annotation-based binary filtering and motif-based linear discriminatory analysis Zané Lombard1*†, Chungoo Park2,3†, Kateryna D Makova2 and Michèle Ramsay1 Abstract Background: Several computational candidate gene selection and prioritization methods have recently been developed. These in silico selection and prioritization techniques are usually based on two central approaches - the examination of similarities to known disease genes and/or the evaluation of functional annotation of genes. Each of these approaches has its own caveats. Here we employ a previously described method of candidate gene prioritization based mainly on gene annotation, in accompaniment with a technique based on the evaluation of pertinent sequence motifs or signatures, in an attempt to refine the gene prioritization approach. We apply this approach to X-linked mental retardation (XLMR), a group of heterogeneous disorders for which some of the underlying genetics is known. Results: The gene annotation-based binary filtering method yielded a ranked list of putative XLMR candidate genes with good plausibility of being associated with the development of mental retardation. In parallel, a motif finding approach based on linear discriminatory analysis (LDA) was employed to identify short sequence patterns that may discriminate XLMR from non-XLMR genes. High rates (>80%) of correct classification was achieved, suggesting that the identification of these motifs effectively captures genomic signals associated with XLMR vs. non-XLMR genes. The computational tools developed for the motif-based LDA is integrated into the freely available genomic analysis portal Galaxy (http://main.g2.bx.psu.edu/).
    [Show full text]