DOCSLIB.ORG

The Genecards Suite Gil Stelzer Gene Information Consolidation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

The GeneCards suite Gil Stelzer Gene information consolidation Disease unification and annotation Pathways integration into SuperPaths Gene set descriptor enrichment NGS Gene-phenotype prioritization www.genecards.org The human gene digital compendium >150 Data Sources AceView WormBase FlyBase ProtoNet HomoloGene AB KEGG InterPro SOURCE GeneLynx NCBI dbSNP HORDE GeneTests PDB MIPS RZPD BLOCKS IMGT LEIDEN PupaSNP GeneLoceuGenesGeneNote HGMD Doctors guide BCGD GeneAtlas MTDB ATLAS TGDB GO Kegg MGD DOts UCSC PubMed bioalma UniProt SwissProt TrEMBL Crow21 HUGO OMIM GenBank Ensembl EntrezGene GDB Blocks HORDE GAD UniGene MINT • Automatic mining • Inter-source integration ~148,000 gene cards entries with “deep links” The human gene compendium Gene-centric information Category Number of Genes 18 sections – including Protein-coding 21,360 RNA genes 98,609 Summaries, Aliases, Pseudogenes 16,337 Diseases, Genomics, Genetic loci 1,819 Gene Clusters 18 Expression, Pathways, Uncategorized 9,770 Localization, Publications Total 147,913 Stelzer et al, Cur. Prot. Bioinformatics 2016 ncRNA All genes ncRNA only 23 data sources Heterogeneity of data All classes ncRNA class-specific Belinky et al, Bioinformatics 2013 Unification of ncRNAs in GeneCards 15k entries 127k entries Positional integration ~99,000 Clustering ncRNAs The ncRNA Grand Unification Gene clusters 132 Genetic loci980 7,350 Uncategorized 21,360 16,337 Protein Pseudo coding genes 15 data sources v3 RNA genes ~70k genes 98,609 v4.7 ~150k genes Enhanced ncRNA classes in GeneCards 10000032 30 28 26 X8 X30 X2 Before unification 24 22 After unification 20 18 1000016 14 Count 12 10 10008 6 1004 102 0 RNA gene class www.malacards.org All names for the same disease Genes for this disease epileptic encephalopathy, early infantile, 1 CDKL5 TPH1 ARX SPTAN1 early infantile epileptic encephalopathy with POMC MECP2 suppression bursts LINC00581 SLC1A3 RDXP2 STXBP1 spasticity - intellectual disability - x-linked epilepsy FOXG1 ABAT PVALB FLNA infantile epileptic-dyskinetic encephalopathy SLC25A22 PTCH1 PHGDH RDX infantile spasms PNKP TLE1 IDUA No disease symbols No systematic name management Three major disease name sources show OMIM low overlap- 6834 need Integration! 2190 512 NIH Rare Disease Diseases Ontology 6416 6047 Name integration Disease Ontology A disease from 15 sources Orphanet compendium GTR 6047 6497 2533 3963 Wikipedia 502 Diseasecard MedlinePlus 405 MalaCards 614 GeneReviews 19,552 Copenhagen 2511 6416 NIH Rare DISEASES Diseases 3467 GeneTests 983 2545 6834 Genetics Home Reference Rappaport et al. (2014) NovoSeek OMIM Cur. Prot. Bioinformatics Name integration process Source hierarchy ~19,600 disease names Textual 15 info sources Canonicalization 85,000 disease strings (names+ aliases) Example – • Liver Cancer • Hepatic Carcinoma 65,000 aliases • Neoplasm of Liver 85,000 Textual Canonization ~19,600 disease disease strings names • Remove non alphanumeric characters • Replace identities (juvenile=childhood) • Remove suffixes (‘s, s, ies) • Eliminate less-informative words (syndrome) • Eliminate prefixes (resistance to) • Translate Greek characters • Unify word order (liver failure = failure, liver) • Unify, but leave in, Roman/Arabic/Latin numerals MalaCards annotation schemes • Interrogating disease resources for classifications, symptoms, variations, drugs… • Searching GeneCards for publications, associated genes • Querying disease-related gene-sets in GeneAnalytics / GeneCards for pathways, phenotypes, compounds, and GO terms • Searching within MalaCards itself, e.g. for related diseases, organ categories… The human disease compendium Disease-centric information Category Number of Genes 14 sections – including Cancer diseases 4,470 Fetal diseases 4,821 Summaries, Aliases, Genes, Genetic diseases 17,334 Anatomical context, Infectious diseases 712 Metabolic diseases 2,594 Pathways, Drugs & Rare diseases 29,140 therapeutics, Publications Stelzer et al, Cur. Prot. Bioinformatics 2016 MalaCards search results Advanced Search 38 Pancreatic Cancer types MalaCards search results Advanced Search 38 Pancreatic Cancer types MalaCards search results A disease family with “Parent” and “children” MalaCards affords category overviews Cancer Cancer GeneticGenetic Genetic (Rare) (Rare)(Rare) Genetic (common) FetalFetal Rare (Non-genetic) Infectious GeneticGenetic Fetal (common) RareRare (common) Cancer (Non(Non-genetic)-genetic) General disease categories Tissue-related disease categories Skin Bone Cardio Neuronal Endocrine Eye 18 tissues Genes with multi- source implications * Elite genes - based on source-count and importance Sources for gene information Elite genes Total: 18,864 diseases Supported also by specific 10,178 genes evidence such as: OMIM: “Molecular basis known” Orphanet: 7,338 7,987 “Causative mutation” without Non-Elite genes with elite GeneCards searches Humsavar: genes “Causative variation” genes in sections such as – GeneTests: Summaries “Genetic Tests” 3,593 Pathways Clinvar with non- Function “Pathogenic” elite genes Publications The challenge of confederating diseases with genes The gene- dis 1 dis 2 dis 3 dis 4 dis 5 dis 6 dis 7 dis 8 dis 9 dis 10 disease gen 1 1 1 1 gen 2 1 matrix gen 3 1 1 gen 4 1 11,791 diseases gen 5 1 10,464 genes gen 6 1 1 1 gen 7 gen 8 1 gen 9 1 gen 10 1 1 The challenge of confederating diseases with genes dis 1 dis 2 dis 3 dis 4 dis 5 dis 6 dis 7 dis 8 dis 9 dis 10 The gene- disease Gen 1 1 1 1 matrix: “mutual Gen 2 1 monogamy” gen 3 1 1 gen 4 1 gen 5 1 gen 6 1 1 1 gen 7 gen 8 1 gen 9 1 gen 10 1 1 The challenge of confederating diseases with genes The gene- dis 1 dis 2 dis 3 dis 4 dis 5 dis 6 dis 7 dis 8 dis 9 dis 10 disease gen 1 1 1 1 Matrix: gen 2 1 Disease gen 3 1 1 with several gen 4 1 gen 5 1 genes gen 6 1 1 1 Gene with gen 7 several gen 8 1 diseases gen 9 1 gen 10 1 1 Max genes per disease Elite Genes ~5000 Before promiscuity filtering ~300 Filtered ~60 Elite genes The ncRNA gene prospect 23k 123k 1.7k 135 20k 1k Total genes 1000000 .36 .003 .73 .06 .02 .07 Fraction with disease 100000 10000 No disease 1000 With disease Genes 100 10 1 Gene category ncRNAs in human diseases Disease Involved ncRNAs ncRNA type Beckwith–Wiedeman syndrome lncRNAs H19 and KCNQ1OT1 lncRNA Silver–Russell syndrome lncRNA H19 lncRNA Deafness miR-96 miRNA Alzheimer's disease miR-29, miR-146 and miR-107 miRNA Alzheimer's disease ncRNA antisense transcript for BACE1 lncRNA Rheumatoid arthritis miR-146a miRNA Transient neonatal diabetes mellitus lncRNA HYMAI lncRNA Amyotropic lateral sclerosis miR-206 miRNA Esteller M., Non-coding RNAs in human disease, Nature Reviews 2011 http://pathcards.genecards.org/ Pathway Pathway Unification Pathway sourcesunification Existing redundancy and ambiguity: Same genes with different pathway names Different genes with same pathway name Each pathway data source shows a different view Creating SuperPaths – Unification in GeneCards of 12 pathway sources Pairwise gene compositional similarity between pathways as a basis for combination of hierarchical and nearest neighborhood clustering Jaccard similarity index , = Belinky et al. Database (Oxford). 2015 ∩ ∪ 0.9 The unification 0.8 algorithm 0.7 0.6 T2 0.5 Redundancy vs 0.4 informativeness 0.3 optimizer 0.2 0.1 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 T1=0.3 =0.7 A combination of hierarchical clustering and nearest neighbor graph representation with 2 cutoffs T1 and T2 (Join all J>T2 (H) and the best if J>T1 (NN)) The SuperPath collection in PathCards Optimal T1, T2 wrong T1, T2 3215 pathways 1073 SuperPaths Novel gene pairs in SuperPaths Gene pairs Source Beneficial novel gene pairs in SuperPaths Count ratio Count Gene pair Count Shared publications https://ga.genecards.org/ A powerful gene set analysis tool Categorized results • Tissue/cell branded expression data • Disease association • Pathways and SuperPaths • Gene Ontologies (GO) connection • Compounds (from several sources) Unique matching algorithms Tissue Expression Example Eye Gene-Set AIPL1, CRB1, Analysis FAM161A, RPE65 Gene-set UNC119 PHO, RPE65 PRPH2 RP1, Mature Rod Cells RPGRIP1 Photoreceptor- Like Cells 193 genes related to Retinitis Pigmentosa Result Categories Results Aggregation and Filters Results Filters Applied Results Links and Additional information Results Results http://varelect.genecards.org/ The augmented functional genome Requires effective bioinformatic tools Whole genome sequencing Whole exome sequencing Introns and UTRs Regulatory Exome ncRNA 2% genes 25% Challenges: annotation, filtration, gene-based interpretation The NGS interpretation cycle DNA Genome mapping Patient NGS VCF Variant (V) V1 G1 Phenotypes V2 G2 calling V3 G2 annotation V4 G3 V5 G4 and V6 G4 V7 G5 filtering G4 (V5) Medium list Genes (G) And other genomic elements Interpretation program Two-tier variant- 25k NGS 1) Filtering containing coding variants • Genetic model gene sifting • Population frequency • Protein damage • Known variants ~100 genes medium list 2) Phenotype- and gene- based interpretation VarElect - A medium gene list interpreter 1-5 genes Stelzer et al, BMC Genomics VarElect 2016 Interpretation Direct mode Gene A Phenotype Gene- gene relations geneA geneB geneC Gene B geneA S1 S2 Indirect mode geneB S1 S3 geneC S2 S3 Guilt by association via sharing of Super-Pathways Mouse phenotypes, tissue expression, paralogy, publications, protein-prtoein interaction, drugs/compounds, domains The VarElect user web interface - data entry User Name diarrhea Disease: Atypical syndromic congenital diarrhea The VarElect Symbolizer
Recommended publications
  • BIOINFORMATICS DOI: 10.1093/Bioinformatics/Btg1030

    BIOINFORMATICS DOI: 10.1093/Bioinformatics/Btg1030

    Vol. 19 Suppl. 1 2003, pages i222–i224 BIOINFORMATICS DOI: 10.1093/bioinformatics/btg1030 GeneLoc: exon-based integration of human genome maps Naomi Rosen, Vered Chalifa-Caspi, Orit Shmueli, Avital Adato, Michal Lapidot, Julie Stampnitzky, Marilyn Safran ∗ and Doron Lancet Weizmann Institute of Science, Rehovot, Israel Received on January 6, 2003; accepted on February 20, 2003 ABSTRACT to provide a comprehensive gene list, NCBI’s LocusLink Motivation: Despite the numerous available whole- contains thousands of model genes, categorized by level genome mapping resources, no comprehensive, inte- and type of support. Even known genes appearing in every grated map of the human genome yet exists. database may have different names in each database. The Results: GeneLoc, software adjunct to GeneCards and biologist must move among databases to figure out which UDB, integrates gene lists by comparing genomic coordi- genes are the same, and which could be a novel gene nates at the exon level and assigns unique and meaningful sought. UCSC’s Genome Browser website maps genes identifiers to each gene. from several sources on the same scale, but the maps are Availability: http://bioinfo.weizmann.ac.il/genecards and not integrated, making it difficult to relate genes from http://genecards.weizmann.ac.il/udb different sources. As stated (Jongeneel, 2000),‘there is an Supplementary information: http://bioinfo.weizmann.ac. urgent need for a human gene index that can be used to il/cards-bin/AboutGCids.cgi, http://genecards.weizmann. identify transcripts unambiguously.’ The author contends ac.il/GeneLocAlg.html that this index should have, among others, the following Contact: [email protected] qualities: comprehensiveness, uniqueness, and stability.

  • Nucleoporin 107, 62 and 153 Mediate Kcnq1ot1 Imprinted Domain Regulation in Extraembryonic Endoderm Stem Cells

    ARTICLE DOI: 10.1038/s41467-018-05208-2 OPEN Nucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells Saqib S. Sachani 1,2,3,4, Lauren S. Landschoot1,2, Liyue Zhang1,2, Carlee R. White1,2, William A. MacDonald3,4, Michael C. Golding 5 & Mellissa R.W. Mann 3,4 1234567890():,; Genomic imprinting is a phenomenon that restricts transcription to predominantly one par- ental allele. How this transcriptional duality is regulated is poorly understood. Here we perform an RNA interference screen for epigenetic factors involved in paternal allelic silen- cing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells. Multiple factors are identified, including nucleoporin 107 (NUP107). To determine NUP107’s role and specificity in Kcnq1ot1 imprinted domain regulation, we deplete Nup107, as well as Nup62, Nup98/96 and Nup153. Nup107, Nup62 and Nup153, but not Nup98/96 depletion, reduce Kcnq1ot1 noncoding RNA volume, displace the Kcnq1ot1 domain from the nuclear periphery, reactivate a subset of normally silent paternal alleles in the domain, alter histone modifications with concomitant changes in KMT2A, EZH2 and EHMT2 occupancy, as well as reduce cohesin interactions at the Kcnq1ot1 imprinting control region. Our results establish an important role for specific nucleoporins in mediating Kcnq1ot1 imprinted domain regulation. 1 Departments of Obstetrics & Gynaecology, and Biochemistry, Western University, Schulich School of Medicine and Dentistry, London, ON N6A 5W9, Canada. 2 Children’s Health Research Institute, London, ON N6C 2V5, Canada. 3 Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. 4 Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
  • Functional Classification of Long Non-Coding Rnas by K-Mer Content

    Functional Classification of Long Non-Coding Rnas by K-Mer Content

    ARTICLES https://doi.org/10.1038/s41588-018-0207-8 Functional classification of long non-coding RNAs by k-mer content Jessime M. Kirk1,2, Susan O. Kim1,8, Kaoru Inoue1,8, Matthew J. Smola3,9, David M. Lee1,4, Megan D. Schertzer1,4, Joshua S. Wooten1,4, Allison R. Baker" "1,10, Daniel Sprague1,5, David W. Collins6, Christopher R. Horning6, Shuo Wang6, Qidi Chen6, Kevin M. Weeks" "3, Peter J. Mucha7 and J. Mauro Calabrese" "1* The functions of most long non-coding RNAs (lncRNAs) are unknown. In contrast to proteins, lncRNAs with similar functions often lack linear sequence homology; thus, the identification of function in one lncRNA rarely informs the identification of function in others. We developed a sequence comparison method to deconstruct linear sequence relationships in lncRNAs and evaluate similarity based on the abundance of short motifs called k-mers. We found that lncRNAs of related function often had similar k-mer profiles despite lacking linear homology, and that k-mer profiles correlated with protein binding to lncRNAs and with their subcellular localization. Using a novel assay to quantify Xist-like regulatory potential, we directly demonstrated that evolutionarily unrelated lncRNAs can encode similar function through different spatial arrangements of related sequence motifs. K-mer-based classification is a powerful approach to detect recurrent relationships between sequence and function in lncRNAs. he human genome expresses thousands of lncRNAs, several This problem extends to the thousands of lncRNAs that lack char- of which regulate fundamental cellular processes. Still, the acterized functions. Toverwhelming majority of lncRNAs lack characterized func- tion and it is likely that physiologically important lncRNAs remain Results to be identified.
  • RPE65 Mutant Dog/ Leber Congenital Amaurosis

    RPE65 Mutant Dog/ Leber Congenital Amaurosis

    Rpe65 mutant dogs Pde6A mutant dogs Cngb1 mutant dogs rAAV RPE65 Mutant Dog/ Leber Congenital Amaurosis Null mutation in Rpe65 retinal function (ERG & dim light vision) Failure of 11-cis retinal supply to photoreceptors (visual cycle) Retina only slow degeneration (S-cones and area centralis degeneration – variable) RPE lipid inclusions 8 Mo 3.5 yr The Visual (Retinoid) Cycle retinal pigment All-trans-retinol epithelium (Vitamin A) RPE65 11-cis-retinal Visual pigments All-trans-retinal rod and cone outer segments All-trans-retinol Gene supplementation therapy for RPE65 Leber Congenital Amaurosis Initial trials in dogs – very successful Outcome in humans Some improvement in visual function Appears to not preserve photoreceptors in longer term Questions Is there preservation of photoreceptors? Why is outcome in humans not so successful? Does RPE65 Gene Therapy Preserve Photoreceptors? Rpe65-/- dogs: Early loss of S-cones Slow LM cone loss Very slow rod loss Exception – region of high density of photoreceptors – rapid loss Gene therapy preservation of photoreceptors Limitations to Human Functional Rescue and Photoreceptor Preservation Hypothesis The dose of gene therapy delivered is a limiting factor for the efficacy of treatment Specific aim To compare the clinical efficacy and the levels of expression of RPE65 protein and the end product of RPE65 function (11-cis retinal) of various doses of RPE65 gene therapy in Rpe65 -/- dogs Methods Tested total dose of 8x108 to 1x1011 vg/eye ERG Scotopic b wave Vision testing % correct choice RPE65 protein expression Dose of gene therapy +/+ 8x108 4x109 2x1010 1x1011 RPE65 GAPDH RPE65 protein expression RPE65/DAPI/ autofluorescence Chromophore levels 11-cis retinal levels undetectable In Rpe65 -/- All-trans retinal Chromophore vs clinical outcomes Scotopic b wave r2 = 0.91 p < 0.0001 Vision testing % correct choice r2 = 0.58 p = 0.02 RPE65 gene expression Human vs.
  • Distinct Visual Pathways Mediatedrosophilalarval Light

    Distinct Visual Pathways Mediatedrosophilalarval Light

    The Journal of Neuroscience, April 27, 2011 • 31(17):6527–6534 • 6527 Behavioral/Systems/Cognitive Distinct Visual Pathways Mediate Drosophila Larval Light Avoidance and Circadian Clock Entrainment Alex C. Keene,1 Esteban O. Mazzoni,1 Jamie Zhen,1 Meg A. Younger,1 Satoko Yamaguchi,1 Justin Blau,1 Claude Desplan,1 and Simon G. Sprecher1,2 1Department of Biology, Center for Developmental Genetics, New York University, New York, New York 10003-6688, and 2Department of Biology, Institute of Cell and Developmental Biology, University of Fribourg, 1700 Fribourg, Switzerland Visual organs perceive environmental stimuli required for rapid initiation of behaviors and can also entrain the circadian clock. The larval eye of Drosophila is capable of both functions. Each eye contains only 12 photoreceptors (PRs), which can be subdivided into two subtypes. Four PRs express blue-sensitive rhodopsin5 (rh5) and eight express green-sensitive rhodopsin6 (rh6). We found that either PR-subtype is sufficient to entrain the molecular clock by light, while only the Rh5-PR subtype is essential for light avoidance. Acetylcholine released from PRs confers both functions. Both subtypes of larval PRs innervate the main circadian pacemaker neurons of the larva, the neuropeptide PDF (pigment-dispersing factor)-expressing lateral neurons (LNs), providing sensory input to control circadian rhythms. How- ever, we show that PDF-expressing LNs are dispensable for light avoidance, and a distinct set of three clock neurons is required. Thus we have identifieddistinctsensoryandcentralcircuitryregulatinglightavoidancebehaviorandclockentrainment.Ourfindingsprovideinsightsintothe coding of sensory information for distinct behavioral functions and the underlying molecular and neuronal circuitry. Introduction sin6 (rh6) (Sprecher et al., 2007; Sprecher and Desplan, 2008).
  • Genome Analysis and Knowledge

    Genome Analysis and Knowledge

    Dahary et al. BMC Medical Genomics (2019) 12:200 https://doi.org/10.1186/s12920-019-0647-8 SOFTWARE Open Access Genome analysis and knowledge-driven variant interpretation with TGex Dvir Dahary1*, Yaron Golan1, Yaron Mazor1, Ofer Zelig1, Ruth Barshir2, Michal Twik2, Tsippi Iny Stein2, Guy Rosner3,4, Revital Kariv3,4, Fei Chen5, Qiang Zhang5, Yiping Shen5,6,7, Marilyn Safran2, Doron Lancet2* and Simon Fishilevich2* Abstract Background: The clinical genetics revolution ushers in great opportunities, accompanied by significant challenges. The fundamental mission in clinical genetics is to analyze genomes, and to identify the most relevant genetic variations underlying a patient’s phenotypes and symptoms. The adoption of Whole Genome Sequencing requires novel capacities for interpretation of non-coding variants. Results: We present TGex, the Translational Genomics expert, a novel genome variation analysis and interpretation platform, with remarkable exome analysis capacities and a pioneering approach of non-coding variants interpretation. TGex’s main strength is combining state-of-the-art variant filtering with knowledge-driven analysis made possible by VarElect, our highly effective gene-phenotype interpretation tool. VarElect leverages the widely used GeneCards knowledgebase, which integrates information from > 150 automatically-mined data sources. Access to such a comprehensive data compendium also facilitates TGex’s broad variant annotation, supporting evidence exploration, and decision making. TGex has an interactive, user-friendly, and easy adaptive interface, ACMG compliance, and an automated reporting system. Beyond comprehensive whole exome sequence capabilities, TGex encompasses innovative non-coding variants interpretation, towards the goal of maximal exploitation of whole genome sequence analyses in the clinical genetics practice. This is enabled by GeneCards’ recently developed GeneHancer, a novel integrative and fully annotated database of human enhancers and promoters.
  • A Multistep Bioinformatic Approach Detects Putative Regulatory

    A Multistep Bioinformatic Approach Detects Putative Regulatory

    BMC Bioinformatics BioMed Central Research article Open Access A multistep bioinformatic approach detects putative regulatory elements in gene promoters Stefania Bortoluzzi1, Alessandro Coppe1, Andrea Bisognin1, Cinzia Pizzi2 and Gian Antonio Danieli*1 Address: 1Department of Biology, University of Padova – Via Bassi 58/B, 35131, Padova, Italy and 2Department of Information Engineering, University of Padova – Via Gradenigo 6/B, 35131, Padova, Italy Email: Stefania Bortoluzzi - [email protected]; Alessandro Coppe - [email protected]; Andrea Bisognin - [email protected]; Cinzia Pizzi - [email protected]; Gian Antonio Danieli* - [email protected] * Corresponding author Published: 18 May 2005 Received: 12 November 2004 Accepted: 18 May 2005 BMC Bioinformatics 2005, 6:121 doi:10.1186/1471-2105-6-121 This article is available from: http://www.biomedcentral.com/1471-2105/6/121 © 2005 Bortoluzzi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results: Novel software (COOP) was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns according to the frequency of their overlapping occurrences.
  • 2007-05 TLE1 Synovial Sarcoma

    2007-05 TLE1 Synovial Sarcoma

    TLE1 Immunostains in the Diagnosis of Synovial Sarcoma May 2007 by Rodney T. Miller, M.D., Director of Immunohistochemistry The diagnosis of synovial sarcoma can be a chal- lenging task, particularly on small biopsy specimens, as the morphologic features of this tumor can be mimicked by a variety of other neoplasms. This month we call attention to a paper published in the February 2007 edition of the American Journal of Surgical Pathology describing the utility of immu- nostains for TLE1 in the diagnosis of this tumor. TLE immunostains are now available at ProPath. Synovial sarcoma occurs in three morphologic varie- ties: monophasic, biphasic, and poorly differentiated. It has been known for some time that synovial sar- coma is associated with a specific chromosomal H&E (left) and TLE1 immunostain (right) on a monophasic translocation, t(X;18), that results in the fusion of the synovial sarcoma. Note the numerous strongly positive nuclei SYT gene on chromosome 18 to either the SSX1 or on the TLE1 immunostain, a typical feature of this tumor. SSX2 gene on the X chromosome, resulting in the production of a SYT-SSX fusion protein. Identifica- In their study, the authors performed TLE1 immu- tion of this translocation in the appropriate setting is nostains on multiple tissue microarrays using two dif- regarded by many to be diagnostic of synovial sar- ferent antibodies (monoclonal and polyclonal), both coma. However, the methodologies used for this performing in a similar fashion. A total of 693 adult purpose (cytogenetics, fluorescent in situ hybridiza- soft tissue tumors were examined, including 94 cases tion, and reverse-transcriptase polymerase chain re- of synovial sarcoma that had documentation of the t action) are not readily available in many diagnostic (X;18) translocation.
  • Full Review Molecular Disease Presentation in Diabetic Nephropathy

    Full Review Molecular Disease Presentation in Diabetic Nephropathy

    Nephrol Dial Transplant (2015) 30: iv17–iv25 doi: 10.1093/ndt/gfv267 Full Review Molecular disease presentation in diabetic nephropathy Downloaded from https://academic.oup.com/ndt/article/30/suppl_4/iv17/2324968 by guest on 25 September 2021 Andreas Heinzel1, Irmgard Mühlberger1, Gil Stelzer2, Doron Lancet2, Rainer Oberbauer3, Maria Martin4 and Paul Perco1 1emergentec biodevelopment GmbH, Vienna, Austria, 2Weizmann Institute of Science, Rehovot, Israel, 3Medical University of Vienna, Vienna, Austria and 4EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, UK Correspondence and offprint requests to: Paul Perco; E-mail: [email protected] ABSTRACT INTRODUCTION Diabetic nephropathy, as the most prevalent chronic disease of Kidney disease is a common problem in patients with diabetes. the kidney, has also become the primary cause of end-stage Depending on the degree of GFR impairment and/or albumin- renal disease with the incidence of kidney disease in type 2 dia- uria, roughly 30% of subjects are affected. As with most betics continuously rising. As with most chronic diseases, the diabetes-associated comorbidities, the pathophysiology is pathophysiology is multifactorial with a number of deregulated multifactorial and the molecular pathways involved in the ini- molecular processes contributing to disease manifestation and tiation and progression constitute a wide and complex as well as progression. Current therapy mainly involves interfering in the redundant network of regulators. Considerable success has renin–angiotensin–aldosterone
  • RPE65 Antibody Order 021-34695924 Orders@Ab-Mart.Com Support 400-6123-828 50Ul Support1@Ab-Mart.Com 100 Ul √ √ Web

    RPE65 Antibody Order 021-34695924 [email protected] Support 400-6123-828 50Ul [email protected] 100 Ul √ √ Web

    TD13248 RPE65 Antibody Order 021-34695924 [email protected] Support 400-6123-828 50ul [email protected] 100 uL √ √ Web www.ab-mart.com.cn Description: Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all- trans-retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore. Essential for the production of 11-cis retinal for both rod and cone photoreceptors. Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT (By similarity). Uniprot:Q16518 Alternative Names： All-trans-retinyl-palmitate hydrolase; LCA 2; LCA2; Leber congenital amaurosis; mRPE 65; mRPE65; p63; rd 12; rd12; Retinal pigment epithelium specific 61 kDa protein; Retinal pigment epithelium specific 65 kDa protein; Retinal pigment epithelium specific protein; Retinal pigment epithelium specific protein 65kDa; Retinal pigment epithelium-specific 65 kDa protein; Retinitis pigmentosa 20; Retinoid isomerohydrolase; Retinol isomerase; RP 20; RP20; RPE 65; RPE65; RPE65_HUMAN; sRPE 65; sRPE65; Specificity: RPE65 Antibody detects endogenous levels of total RPE65. Reactivity:Human, Mouse, Rat Source:Rabbit Mol.Wt.: 60kD; 61kDa(Calculated).
  • Depletion of Kcnq1ot1 Non-Coding RNA Does Not Affect Imprinting Maintenance in Stem Cells Michael C

    Depletion of Kcnq1ot1 Non-Coding RNA Does Not Affect Imprinting Maintenance in Stem Cells Michael C

    DEVELOPMENT AND STEM CELLS RESEARCH ARTICLE 3667 Development 138, 3667-3678 (2011) doi:10.1242/dev.057778 © 2011. Published by The Company of Biologists Ltd Depletion of Kcnq1ot1 non-coding RNA does not affect imprinting maintenance in stem cells Michael C. Golding1,2,3,*,†, Lauren S. Magri1,2,3,†, Liyue Zhang2,3, Sarah A. Lalone1,2,3, Michael J. Higgins4 and Mellissa R. W. Mann1,2,3,‡ SUMMARY To understand the complex regulation of genomic imprinting it is important to determine how early embryos establish imprinted gene expression across large chromosomal domains. Long non-coding RNAs (ncRNAs) have been associated with the regulation of imprinting domains, yet their function remains undefined. Here, we investigated the mouse Kcnq1ot1 ncRNA and its role in imprinted gene regulation during preimplantation development by utilizing mouse embryonic and extra-embryonic stem cell models. Our findings demonstrate that the Kcnq1ot1 ncRNA extends 471 kb from the transcription start site. This is significant as it raises the possibility that transcription through downstream genes might play a role in their silencing, including Th, which we demonstrate possesses maternal-specific expression during early development. To distinguish between a functional role for the transcript and properties inherent to transcription of long ncRNAs, we employed RNA interference-based technology to deplete Kcnq1ot1 transcripts. We hypothesized that post-transcriptional depletion of Kcnq1ot1 ncRNA would lead to activation of normally maternal-specific protein-coding genes on the paternal chromosome. Post-transcriptional short hairpin RNA-mediated depletion in embryonic stem, trophoblast stem and extra-embryonic endoderm stem cells had no observable effect on the imprinted expression of genes within the domain, or on Kcnq1ot1 imprinting center DNA methylation, although a significant decrease in Kcnq1ot1 RNA signal volume in the nucleus was observed.
  • Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

    Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

    International Journal of Molecular Sciences Review Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease Fukiko Kitani-Morii 1,2,* and Yu-ichi Noto 2 1 Department of Molecular Pathobiology of Brain Disease, Kyoto Prefectural University of Medicine, Kyoto 6028566, Japan 2 Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto 6028566, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-75-251-5793 Received: 31 August 2020; Accepted: 6 October 2020; Published: 8 October 2020 Abstract: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic testing. Advances in genetic testing technology have revealed the genetic heterogeneity of CMT; more than 100 genes containing the disease causative mutations have been identified. Because a single genetic alteration in CMT leads to progressive neurodegeneration, studies of CMT patients and their respective models revealed the genotype-phenotype relationships of targeted genes. Conventionally, rodents and cell lines have often been used to study the pathogenesis of CMT. Recently, Drosophila has also attracted attention as a CMT model. In this review, we outline the clinical characteristics of CMT, describe the advantages and disadvantages of using Drosophila in CMT studies, and introduce recent advances in CMT research that successfully applied the use of Drosophila, in areas such as molecules associated with mitochondria, endosomes/lysosomes, transfer RNA, axonal transport, and glucose metabolism.