DOCSLIB.ORG

ADSSL1 Mutation Relevant to Autosomal Recessive Adolescent Onset Distal Myopathy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ADSSL1 Mutation Relevant to Autosomal Recessive Adolescent Onset Distal Myopathy RESEARCH ARTICLE ADSSL1 Mutation Relevant to Autosomal Recessive Adolescent Onset Distal Myopathy Hyung Jun Park, MD,1,2 Young Bin Hong, PhD,3 Young-Chul Choi, MD, PhD,2 Jinho Lee, MD,3 Eun Ja Kim, MD,3 Ji-Su Lee,4 Won Min Mo, MS,3 Soo Mi Ki, MS,4 Hyo In Kim,4 Hye Jin Kim,5 Young Se Hyun, PhD,5 Hyun Dae Hong,5 Kisoo Nam,6 Sung Chul Jung, MD, PhD,7 Sang-Beom Kim, MD, PhD,8 Se Hoon Kim, MD, PhD,9 Deok-Ho Kim, PhD,10 Ki-Wook Oh, MD,11 Seung Hyun Kim, MD, PhD,11 Jeong Hyun Yoo, MD, PhD,12 Ji Eun Lee, PhD,4,13 Ki Wha Chung, PhD,5 and Byung-Ok Choi, MD, PhD3,4,14 Objective: Distal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent onset distal myopathy. Methods: Four patients from 2 unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis. Results: Patients had an adolescent onset distal myopathy phenotype that included distal dominant weakness, facial muscle weakness, rimmed vacuoles, and mild elevation of serum creatine kinase. Exome sequencing identified com- pletely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1, which encodes a muscle-specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the muta- tion sites were located in well-conserved regions. Both the D304N and I350fs mutations in ADSSL1 led to decreased enzymatic activity. The knockdown of the Adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knockdown zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect. Interpretation: We suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adoles- cent onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics. ANN NEUROL 2016;79:231–243 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24550 Received Jun 8, 2015, and in revised form Oct 7, 2015. Accepted for publication Oct 18, 2015. Address correspondence to Dr Byung-Ok Choi, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected]; Dr Ki Wha Chung, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 32588, Korea. E-mail: [email protected]; Dr Ji Eun Lee, Samsung Advanced Institute for Health Science & Tech., Samsung Genome Institute (SGI), Sam- sung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. E-mail: [email protected] From the 1Department of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea; 2Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; 3Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 4Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea; 5Department of Biological Science, Kongju National University, Gongju, South Korea; 6Department of Chemistry, New York University, New York, NY; 7Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea; 8Department of Neurology, Kyung Hee University College of Medicine, Kangdong Hospital, Seoul, South Korea; 9Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea; 10Department of Bioengineering, University of Washington, Seattle, WA; 11Department of Neurology, College of Medicine, Hanyang University, Seoul, South Korea; 12Department of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, South Korea; 13Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea; and 14Neuroscience Center, Samsung Medical Center, Seoul, South Korea VC 2015 American Neurological Association 231 ANNALS of Neurology istal myopathy is a clinically and genetically hetero- DYSF, and Miyoshi muscular dystrophy 3 caused by Dgeneous group of predominantly distal muscle ANO5.2–5 Distal nebulin myopathy and GNE myopathy degenerative diseases. Distal myopathy is classified into have childhood to early adult onset, and initially show subgroups based on clinical aspects and genetic causes. ankle dorsiflexor weakness and a mild elevation in serum To date, > 15 causative genes have been reported in dif- creatine kinase (CK).2,3 Conversely, Miyoshi myopathy ferent forms of distal myopathies.1 These genes encode or Miyoshi muscular dystrophy 3 have adult onset, pre- proteins that have various functions in all areas of muscle dominant ankle plantar flexor weakness, no facial muscle cell biology, including sarcomeric integrity and function involvement, and severe elevation in serum CK.4,5 Recent (MYOT, TTN, MYH7, NEB, LDB3, and FLNC), sialic whole exome or targeted next generation sequencing has acid biosynthesis (GNE), DNA/RNA-binding proteins proven to be an efficient tool to identify rare genetic (TIA1), membrane repair (DYSF), guanosine triphospha- causes in distal myopathies. We have identified a couple tase (DNM2), vesicular trafficking and signal transduc- of compound heterozygous mutations in ADSSL1 by tion (CAV3), calcium-activated ionic channel (ANO5), exome sequencing, and suggest they are the underlying mitotic progression (KLHL9), and chaperone proteins cause in 2 autosomal recessive distal myopathy families (VCP and DNAJB6).2–17 Recent genomic analysis has with adolescent onset. This suggestion was further con- steadily updated novel genetic causes; however, consider- firmed with an in vitro assay using mouse myoblast cells able myopathy patients still wait for the genetic cause to and an in vivo assay using Adssl1 knockdown zebrafish. be uncovered. Most types of distal myopathies are associ- ated with autosomal dominant inheritance, but 4 types Subjects and Methods are associated with autosomal recessive inheritance: distal Patients nebulin myopathy caused by NEB mutations; GNE This study included a total of 10 members from 2 unrelated myopathy caused by GNE; Miyoshi myopathy caused by adolescent onset distal myopathy families in Korea (family IDs: FIGURE 1: Two autosomal recessive distal myopathy families with novel compound heterozygous mutations in ADSSL1. (A) Pedigrees of 2 distal myopathy families FC628 and FC630. Genotypes of 2 ADSSL1 mutations are indicated at the bottom of each examined individual. Arrows and asterisks indicate the proband of each family and individual whose genome was applied for exome sequencing (squares: male; circles: female; filled: affected; and nonfilled: unaffected). (B) Domain structure of adeny- losuccinate synthase-like 1 (ADSSL1) protein. ADSSL1 contains both a guanosine triphosphate–binding domain (GTP) and an adenylosuccinate synthase domain (ASS). Both identified mutations are located on the ASS domain. (C) Sequencing chromato- grams of c.910G>A (p.D304N) and c.1048delA (p.I350fs) mutations in ADSSL1. Arrows indicate mutation sites (Mut 5 mutant; WT 5 wild type). (D) Conservation analysis of amino acid sequences on the p.D304N mutation sites. The mutation site and sur- rounding regions are highly conserved from human to yeast species. 232 Volume 79, No. 2 Park et al: ADSSL1 and Distal Myopathy FC628 and FC630; Fig 1A). Three and 1 affected members thickness 5 4–5mm, slice gap 5 0.5–1.0 mm). The following were included from FC628 and FC630, respectively. The phe- protocol was used for all patients: T1-weighted spin-echo (SE) notype seemed to be inherited by the autosomal recessive mode (repetition time [TR] 5 570–650 milliseconds, echo time because their parents were unaffected, and no other patient was [TE] 5 14–20 milliseconds, 512 matrixes), T2-weighted SE identified from the close relatives of the 2 families. This study (TR 5 2,800–4,000 milliseconds, TE 5 96–99 milliseconds, also included 500 healthy controls who had no clinical features 512 matrixes), and fat-suppressed T2-weighted SE or family history of distal myopathy, which was confirmed after (TR 5 3,090–4,900 milliseconds, TE 5 85–99 milliseconds, careful clinical and electrophysiological examinations. Written 512 matrixes). informed consent was obtained from all participants according to the protocol approved by the institutional review board for Sung- Exome Sequencing and Filtering of Variants kyunkwan University, Samsung Medical Center. Exome sequencing was performed with the Human SeqCap EZ Human Exome Library v3.0 (Roche/NimbleGen, Madison, Clinical and Electrophysiological Examinations WI), and the HiSeq2000 and HiSeq2500 Genome Analyzer Two independent neurologists did the clinical evaluation. Clini- (Illumina, San Diego, CA) for 6 samples from the FC628 fam- cal information included assessments of age at onset, muscle ily (3 affected: II-1,II-2, II-4; 3 unaffected: I-1, I-2, II-3) and impairments, sensory loss, deep tendon reflexes, and muscle for 1 sample from the FC630 family (affected: II-2). The Uni- atrophy. The muscle strength of the flexor and extensor muscles versity of
Load more

Recommended publications
  • The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy
    International Journal of Molecular Sciences Review The Role of Z-disc Proteins in Myopathy and Cardiomyopathy Kirsty Wadmore 1,†, Amar J. Azad 1,† and Katja Gehmlich 1,2,* 1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (K.W.); [email protected] (A.J.A.) 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected]; Tel.: +44-121-414-8259 † These authors contributed equally. Abstract: The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Neuromuscular Disorders Neurology in Practice: Series Editors: Robert A
    Neuromuscular Disorders neurology in practice: series editors: robert a. gross, department of neurology, university of rochester medical center, rochester, ny, usa jonathan w. mink, department of neurology, university of rochester medical center,rochester, ny, usa Neuromuscular Disorders edited by Rabi N. Tawil, MD Professor of Neurology University of Rochester Medical Center Rochester, NY, USA Shannon Venance, MD, PhD, FRCPCP Associate Professor of Neurology The University of Western Ontario London, Ontario, Canada A John Wiley & Sons, Ltd., Publication This edition fi rst published 2011, ® 2011 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientifi c, Technical and Medical business to form Wiley-Blackwell. Registered offi ce: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offi ces: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offi ces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identifi ed as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • Distal Myopathies a Review: Highlights on Distal Myopathies with Rimmed Vacuoles
    Review Article Distal myopathies a review: Highlights on distal myopathies with rimmed vacuoles May Christine V. Malicdan, Ikuya Nonaka Department of Neuromuscular Research, National Institutes of Neurosciences, National Center of Neurology and Psychiatry, Tokyo, Japan Distal myopathies are a group of heterogeneous disorders Since the discovery of the gene loci for a number classiÞ ed into one broad category due to the presentation of distal myopathies, several diseases previously of weakness involving the distal skeletal muscles. The categorized as different disorders have now proven to recent years have witnessed increasing efforts to identify be the same or allelic disorders (e.g. distal myopathy the causative genes for distal myopathies. The identiÞ cation with rimmed vacuoles and hereditary inclusion body of few causative genes made the broad classiÞ cation of myopathy, Miyoshi myopathy and limb-girdle muscular these diseases under “distal myopathies” disputable and dystrophy type 2B (LGMD 2B). added some enigma to why distal muscles are preferentially This review will focus on the most commonly affected. Nevertheless, with the clariÞ cation of the molecular known and distinct distal myopathies, using a simple basis of speciÞ c conditions, additional clues have been classification: distal myopathies with known molecular uncovered to understand the mechanism of each condition. defects [Table 1] and distal myopathies with unknown This review will give a synopsis of the common distal causative genes [Table 2]. The identification of the myopathies, presenting salient facts regarding the clinical, genes involved in distal myopathies has broadened pathological, and molecular aspects of each disease. Distal this classification into sub-categories as to the location myopathy with rimmed vacuoles, or Nonaka myopathy, will of encoded proteins: sarcomere (titin, myosin); plasma be discussed in more detail.
    [Show full text]
  • Interactions Between APOBEC3 and Murine Retroviruses: Mechanisms of Restriction and Drug Resistance
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Interactions Between APOBEC3 and Murine Retroviruses: Mechanisms of Restriction and Drug Resistance Alyssa Lea MacMillan University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Virology Commons Recommended Citation MacMillan, Alyssa Lea, "Interactions Between APOBEC3 and Murine Retroviruses: Mechanisms of Restriction and Drug Resistance" (2013). Publicly Accessible Penn Dissertations. 894. https://repository.upenn.edu/edissertations/894 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/894 For more information, please contact [email protected]. Interactions Between APOBEC3 and Murine Retroviruses: Mechanisms of Restriction and Drug Resistance Abstract APOBEC3 proteins are important for antiretroviral defense in mammals. The activity of these factors has been well characterized in vitro, identifying cytidine deamination as an active source of viral restriction leading to hypermutation of viral DNA synthesized during reverse transcription. These mutations can result in viral lethality via disruption of critical genes, but in some cases is insufficiento t completely obstruct viral replication. This sublethal level of mutagenesis could aid in viral evolution. A cytidine deaminase-independent mechanism of restriction has also been identified, as catalytically inactive proteins are still able to inhibit infection in vitro. Murine retroviruses do not exhibit characteristics of hypermutation by mouse APOBEC3 in vivo. However, human APOBEC3G protein expressed in transgenic mice maintains antiviral restriction and actively deaminates viral genomes. The mechanism by which endogenous APOBEC3 proteins function is unclear. The mouse provides a system amenable to studying the interaction of APOBEC3 and retroviral targets in vivo.
    [Show full text]
  • The MOGE(S) Classification of Cardiomyopathy for Clinicians
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 64, NO. 3, 2014 ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00 PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.05.027 THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW The MOGE(S) Classification of Cardiomyopathy for Clinicians Eloisa Arbustini, MD,* Navneet Narula, MD,y Luigi Tavazzi, MD, PHD,z Alessandra Serio, MD, PHD,* Maurizia Grasso, BD, PHD,* Valentina Favalli, PHD,* Riccardo Bellazzi, ME, PHD,x Jamil A. Tajik, MD,k Robert O. Bonow, MD,{ Valentin Fuster, MD, PHD,# Jagat Narula, MD, PHD# ABSTRACT Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and
    [Show full text]
  • Global Gene Expression Analysis of the Mouse Colonic Mucosa Treated
    BMC Cancer BioMed Central Research article Open Access Global gene expression analysis of the mouse colonic mucosa treated with azoxymethane and dextran sodium sulfate Rikako Suzuki1, Shingo Miyamoto2, Yumiko Yasui1, Shigeyuki Sugie1 and Takuji Tanaka*1 Address: 1Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan and 2Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan Email: Rikako Suzuki - [email protected]; Shingo Miyamoto - [email protected]; Yumiko Yasui - y-yasui@kanazawa- med.ac.jp; Shigeyuki Sugie - [email protected]; Takuji Tanaka* - [email protected] * Corresponding author Published: 17 May 2007 Received: 10 July 2006 Accepted: 17 May 2007 BMC Cancer 2007, 7:84 doi:10.1186/1471-2407-7-84 This article is available from: http://www.biomedcentral.com/1471-2407/7/84 © 2007 Suzuki 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: Chronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. To shed light on the alterations in global gene expression in the background of inflammation-related colon cancer and gain further insights into the molecular mechanisms underlying inflammation-related colon carcinogenesis, we conducted a comprehensive DNA microarray analysis using our model.
    [Show full text]
  • Table SII. Significantly Differentially Expressed Mrnas of GSE23558 Data Series with the Criteria of Adjusted P<0.05 And
    Table SII. Significantly differentially expressed mRNAs of GSE23558 data series with the criteria of adjusted P<0.05 and logFC>1.5. Probe ID Adjusted P-value logFC Gene symbol Gene title A_23_P157793 1.52x10-5 6.91 CA9 carbonic anhydrase 9 A_23_P161698 1.14x10-4 5.86 MMP3 matrix metallopeptidase 3 A_23_P25150 1.49x10-9 5.67 HOXC9 homeobox C9 A_23_P13094 3.26x10-4 5.56 MMP10 matrix metallopeptidase 10 A_23_P48570 2.36x10-5 5.48 DHRS2 dehydrogenase A_23_P125278 3.03x10-3 5.40 CXCL11 C-X-C motif chemokine ligand 11 A_23_P321501 1.63x10-5 5.38 DHRS2 dehydrogenase A_23_P431388 2.27x10-6 5.33 SPOCD1 SPOC domain containing 1 A_24_P20607 5.13x10-4 5.32 CXCL11 C-X-C motif chemokine ligand 11 A_24_P11061 3.70x10-3 5.30 CSAG1 chondrosarcoma associated gene 1 A_23_P87700 1.03x10-4 5.25 MFAP5 microfibrillar associated protein 5 A_23_P150979 1.81x10-2 5.25 MUCL1 mucin like 1 A_23_P1691 2.71x10-8 5.12 MMP1 matrix metallopeptidase 1 A_23_P350005 2.53x10-4 5.12 TRIML2 tripartite motif family like 2 A_24_P303091 1.23x10-3 4.99 CXCL10 C-X-C motif chemokine ligand 10 A_24_P923612 1.60x10-5 4.95 PTHLH parathyroid hormone like hormone A_23_P7313 6.03x10-5 4.94 SPP1 secreted phosphoprotein 1 A_23_P122924 2.45x10-8 4.93 INHBA inhibin A subunit A_32_P155460 6.56x10-3 4.91 PICSAR P38 inhibited cutaneous squamous cell carcinoma associated lincRNA A_24_P686965 8.75x10-7 4.82 SH2D5 SH2 domain containing 5 A_23_P105475 7.74x10-3 4.70 SLCO1B3 solute carrier organic anion transporter family member 1B3 A_24_P85099 4.82x10-5 4.67 HMGA2 high mobility group AT-hook 2 A_24_P101651
    [Show full text]
  • Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins
    microorganisms Review Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins Yoshiyuki Hakata 1,* and Masaaki Miyazawa 1,2 1 Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan; [email protected] 2 Kindai University Anti-Aging Center, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan * Correspondence: [email protected]; Tel.: +81-72-367-7660 Received: 8 December 2020; Accepted: 9 December 2020; Published: 12 December 2020 Abstract: Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3. Keywords: APOBEC3; deaminase-independent antiretroviral function; innate immunity 1.
    [Show full text]
  • 1 APOBEC-Mediated Mutagenesis in Urothelial Carcinoma Is Associated
    bioRxiv preprint doi: https://doi.org/10.1101/123802; this version posted April 4, 2017. 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. APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response Alexander P. Glaser MD, Damiano Fantini PhD, Kalen J. Rimar MD, Joshua J. Meeks MD PhD APG, DF, KJR, JJM: Northwestern University, Department of Urology, Chicago, IL, 60607 Running title: APOBEC mutagenesis in bladder cancer *Corresponding author: Joshua J. Meeks, MD PhD 303 E. Chicago Ave. Tarry 16-703 Chicago, IL 60611 Email: [email protected] Keywords (4-6): • Urinary bladder neoplasms • APOBEC Deaminases • Mutagenesis • DNA damage • Interferon Abbreviations and Acronyms: TCGA – The Cancer Genome Atlas ssDNA – single stranded DNA APOBEC –apolipoprotein B mRNA editing catalytic polypeptide-like GCAC – Genome Data Analysis Center MAF – mutation annotation format “APOBEC-high” – tumors enriched for APOBEC mutagenesis “APOBEC-low” – tumors not enriched for APOBEC mutagenesis 1 bioRxiv preprint doi: https://doi.org/10.1101/123802; this version posted April 4, 2017. 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: Background: The APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival.
    [Show full text]
  • AID Downregulation Is a Novel Function of the DNMT Inhibitor 5-Aza-Deoxycytidine
    www.impactjournals.com/oncotarget/ Oncotarget, January, Vol. 5, No. 1 AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine Chiou-Tsun Tsai1, Pei-Ming Yang1, Ting-Rong Chern3, Shu-Hui Chuang1, Jung-Hsin Lin2,3,4, Lars Klemm5, Markus Müschen5 and Ching-Chow Chen1 1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Research Center for Applied Sciences, Academia Sinica, Taipei, Taiwan 4 Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan 5 Department of Laboratory Medicine, University of California San Francisco, San Francisco, California Correspondence to: Ching-Chow Chen, email: [email protected] Keywords: AID, 5-aza-CdR, Zebularine, DNMT1 Received: August 23, 2013 Accepted: November 23, 2013 Published: November 25, 2013 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation (SHM) and class switch recombination (CSR) in immunoglobulin genes. However, AID can also cause mutations in host genes and contribute to cancer progression and drug resistance. In this study, molecular docking showed the interaction of free 5-aza-CdR and Zebularine (Zeb) with AID. However, only 5-aza-CdR-incorporated ssDNA bound to the active site of AID and inhibited AID expression through proteasomal degradation. 5-aza-CdR demonstrated cytotoxicity against AID-positive and -negative hematopoietic cancer cells.
    [Show full text]