PDF Hosted at the Radboud Repository of the Radboud University Nijmegen

Total Page:16

File Type:pdf, Size:1020Kb

PDF Hosted at the Radboud Repository of the Radboud University Nijmegen PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/30002 Please be advised that this information was generated on 2021-10-03 and may be subject to change. of Sharola Dharmaraj amaurosis analysis and congenital Clinical molecular Leber Clinical and molecular analysis of Leber congenital amaurosis Sharola Dharmaraj Clinical and molecular analysis of Leber congenital amaurosis Sharola Dharmaraj SSharolaharola BBW.inddW.indd 1 229-May-079-May-07 110:45:200:45:20 AAMM Clinical and molecular analysis of Leber congenital amaurosis PhD thesis Radboud University Nijmegen Medical Centre Sharola Dharmaraj ISBN: 978-90-9021-989-9 © 2007 S. Dharmaraj All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, by print or otherwise, without permission in writing from the author. Cover image: Fundus in LCA5-associated LCA (K.Klima) Print and layout by: Optima Grafi sche Communicatie, Rotterdam SSharolaharola BBW.inddW.indd 2 229-May-079-May-07 110:45:220:45:22 AAMM Clinical and molecular analysis of Leber congenital amaurosis Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnifi cus prof. mr. S.C.J.J Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 2 juli 2007 om 13.30 uur precies door Sharola Dharmaraj geboren op 11 december 1961 te India SSharolaharola BBW.inddW.indd 3 229-May-079-May-07 110:45:220:45:22 AAMM Promotor: Prof. dr. F.P.M. Cremers Copromotor: Dr. R.K. Koenekoop (McGill University, Montreal) Manuscriptcommissie: Prof. dr. B.G.M. van Engelen (Voorzitter) Dr. R. Allikmets (Columbia University, New York) Dr. C.B. Hoyng SSharolaharola BBW.inddW.indd 4 229-May-079-May-07 110:45:220:45:22 AAMM Clinical and molecular analysis of Leber congenital amaurosis A scientifi c essay in Medical Sciences Doctoral thesis to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnifi cus, prof. dr. S.C.J.J. Kortmann according to the decision of the Council of Deans to be defended in public on Monday, 2 July 2007 at 13.30 hours by Sharola Dharmaraj born in India on 11 December 1961 SSharolaharola BBW.inddW.indd 5 229-May-079-May-07 110:45:220:45:22 AAMM Supervisor: Prof. dr. F.P.M. Cremers Co-supervisor: Dr. R.K. Koenekoop (McGill University, Montreal) Doctoral Thesis Committee: Prof. dr. B.G.M. van Engelen (Chairman) Dr. R. Allikmets (Columbia University, New York) Dr. C.B. Hoyng SSharolaharola BBW.inddW.indd 6 229-May-079-May-07 110:45:220:45:22 AAMM Dedicated to everyone involved with LCA everywhere SSharolaharola BBW.inddW.indd 7 229-May-079-May-07 110:45:220:45:22 AAMM SSharolaharola BBW.inddW.indd 8 229-May-079-May-07 110:45:220:45:22 AAMM Table of contents Abbreviations 13 Chapter 1. Introduction 17 1.1 Ocular embryology 19 1.2 Genetics of retinal disease 20 1.2.1 Autosomal dominant inheritance 21 1.2.2 Autosomal recessive inheritance 23 1.2.3 X-linked Inheritance 23 1.2.4 Digenic Inheritance 23 1.2.5 Uniparental isodisomy (UPD) 24 1.3 Tools and methods for gene identifi cation 24 1.3.1 Genetic markers 24 1.3.2 Cloning approaches 25 1.3.2.1 Functional cloning 25 1.3.2.2 Positional cloning 25 1.3.2.2.1 Mapping of the candidate region 26 1.3.2.2.2 Identifying candidate genes 28 1.3.3 Mutation Analysis 30 1.3.3.1 Mutations 30 1.3.3.2 Polymorphisms 30 1.3.3.3 Mutation detection 31 1.3.4 Bioinformatics 36 1.4 Retinal anatomy 37 1.4.1 Retinal structure 38 1.4.1.1 Photoreceptor cells and function 39 1.4.1.2 Function and structure of the retinal pigment epithelium 41 1.4.2 Retinal physiology 42 1.4.2.1 Phototransduction 43 1.4.2.2 Retinoid metabolism 44 1.5 Retinal disease 46 1.5.1 Clinical diagnosis of retinal disorders 47 1.5.1.1 Imaging 47 1.5.1.2 Electrophysiology 48 1.5.2 Phenotype of retinal disorders 50 1.5.3 Pathology of retinal degeneration 52 1.5.4 Animal models and retinal degeneration 53 1.6 Aim and outline of this thesis 54 Table of contents 9 SSharolaharola BBW.inddW.indd 9 229-May-079-May-07 110:45:220:45:22 AAMM Chapter 2. Leber congenital amaurosis 55 2.1 Clinical evaluation 57 2.2 Clinical associations 61 2.3 Genes and loci 64 2.4 Pathogenesis 73 2.5 Animal models of LCA 75 2.6 Genotype-Phenotype correlation 80 2.7 Molecular genetic diagnosis 88 2.8 Treatment strategies 90 2.8.1 Ethical considerations 90 2.8.2 Current management 91 2.8.3 Novel treatment 92 2.8.3.1 Gene therapy 92 2.8.3.2 Pharmacotherapy 94 2.8.3.3 Cell transplantation 95 2.8.3.4 Retinal prosthesis 96 2.8.3.5 Cortical devices 97 References 98 Web Sources and Bioinformatics URLs 123 Chapter 3 A novel locus for Leber congenital amaurosis maps to chromosome 6q 125 Am J Hum Genet. 2000, 66(1):319-26. Chapter 4 Mutational analysis and clinical correlation in Leber congenital amaurosis 135 Ophthalmic Genet. 2000, 21(3):135-50. Chapter 5 The phenotype of Leber congenital amaurosis in patients with AIPL1 153 mutations Arch Ophthalmol. 2004, 122(7):1029-37. Chapter 6 A missense mutation in GUCY2D acts as a genetic modifi er in RPE65-related 165 Leber congenital amaurosis Ophthalmic Genet. 2004, 25(3):205-7. Chapter 7 Genotyping microarray (disease chip) for Leber congenital amaurosis: 181 detection of modifi er alleles Invest Ophthalmol Vis Sci. 2005, 46(9):3052-9. 10 SSharolaharola BBW.inddW.indd 1100 229-May-079-May-07 110:45:220:45:22 AAMM Chapter 8. Discussion 191 8.1 A novel locus for LCA: LCA 5 193 8.2 Genotype-Phenotype considerations 194 8.2.1 General observations 194 8.2.2 Locus or gene-based phenotypical characteristics 194 8.2.3 Recurrence of LCA sequence variants 195 8.2.4 Frequency of LCA variants 196 8.3 Modifi er effects 196 8.4 Future direction 197 8.5 Conclusion 198 Chapter 9. Summary 203 9.1 Summary 203 9.2 Samenvatting 203 Acknowledgement 209 Publications list 211 Biographical sketch 213 Table of contents 11 SSharolaharola BBW.inddW.indd 1111 229-May-079-May-07 110:45:220:45:22 AAMM SSharolaharola BBW.inddW.indd 1122 229-May-079-May-07 110:45:230:45:23 AAMM Abbreviations AAV Adeno-associated virus ABCR Photoreceptor specifi c ATP binding cassette AD Autosomal dominant ADRP Autosomal dominant retinitis pigmentosa AIPL1 Arylhydrocarbon-interacting receptor protein-like APEX Arrayed primer extension AR Autosomal recessive ARMD Age-related macular dystrophy ARRP Autosomal recessive retinitis pigmentosa BBS Bardet Biedl syndrome bHLH basic helix loop helix β PDE Beta phosphodiesterase bps base pairs cDNA complementary deoxyribose nucleic acid CF Counting fi ngers cGMP Cyclic guanosine monophosphate CHX10 Ceh-10 homeo domain containing homolog cM centiMorgan CORD Cone-rod dystrophy CRALBP Cellular retinaldehyde-binding protein CRB1 Crumbs homologue-1 CRBP Cellular retinal binding protein CRX Cone-rod homeobox CSNB Congenital stationary night blindness DNA Deoxyribonucleic acid EFS Elongation factors ePCR Electronic polymerase chain reaction ERG Electroretinogram EST Expressed sequence tags GC1 Guanylate cyclase 1 GCAP 1 & 2 Guanylyl cyclase activating proteins 1 & 2 GDNF Glia derived neurotrophic factor GDP Guanine diphosphate GMP Guanine monophosphate cGMP Cyclic guanine monophosphate GTP Guanine triphosphate GUCY2D Guanylate cyclase 2D HM Hand movements ISCEV International Society for Clinical Electrophysiology of Vision IL 1b Interleukin 1b IMPG1 Interphotoreceptor matrix proteoglycan 1 IMPDH1 Inosine 5’- phosphate dehydogenase1 IRBP Interphotoreceptor binding protein JBTS1 Joubert syndrome 1 kb kilobase Abbreviations 13 SSharolaharola BBW.inddW.indd 1133 229-May-079-May-07 110:45:230:45:23 AAMM LCA Leber congenital amaurosis LOD Logarithm of the odds ratio LP Light perception LRAT Lecithin retinol acyltransferase MERG Multifocal electroretinogram MERTK c-mer proto-oncogene tyrosin kinase MITF Micophthalmia associated transcription factor MPS-VII Mucopolysaccharide type VII MRI Magnetic resonance imaging mRNA messenger ribonucleic acid mRPE65 membrane-associated retinal pigment epithelium protein 65 NEDD8 Neural precursor cell expressed, developmentally down-regulated 8 NPAPHP3 Nephronophthisis homolog 3 (Caenorhabditis elegans) NPHP Nephronophthisis NPNH4 Nephronophthisis homolog 4 (Caenorhabditis elegans) NRL Neural retina leucine -zipper OCT Ocular coherence tomography otd Orthodenticle related homeodomain OTX Orthodenticle related homeobox PAX6 Paired box 6 PCR Polymerase chain reaction PDE Phosphodiesterase PERG Pattern electroretinogram PET Positron emission tomography PEX Peroxin PRC Photoreceptor cell RBP Retinal binding protein RCS Royal college of surgeons RDH12 Retinol dehydrogenase 12 RDS Retinal degeneration slow RETGC Retinal guanylate cyclase RFLP Restriction fragment length polymorphism RHO Rhodopsin RLBP1 Retinal binding protein 1 RP Retinitis pigmentosa RP12 Retinitis pigmentosa type 12 RPE Retinal pigment epithelium RPE65 Retinal pigment epithelium specifi c 65kD protein RPGR Retinitis pigmentosa guanosine triphosphate (GTPase) regulator RPGRIP1 Retinitis pigmentosa guanosine triphosphate (GTPase) regulator interacting protein 1 RX Retinal homeobox SAGE Serial analysis of gene expression SLS Senior Løken syndrome SNP Single nucleotide polymorphism sRPE65 Soluble retinal pigment epithelium protein 65 SSCP Single strand conformational polymorphism SSRs Short sequence repeats 14 SSharolaharola
Recommended publications
  • Human Cellular Retinaldehyde-Binding Protein Has Secondary Thermal 9-Cis-Retinal Isomerase Activity
    See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/259313787 Human Cellular Retinaldehyde-Binding Protein Has Secondary Thermal 9-cis-Retinal Isomerase Activity Article in Journal of the American Chemical Society · January 2014 DOI: 10.1021/ja411366w · Source: PubMed CITATIONS READS 6 123 12 authors, including: Christin Bolze Rachel E. Helbling Vifor Pharma 13 PUBLICATIONS 21 CITATIONS 3 PUBLICATIONS 13 CITATIONS SEE PROFILE SEE PROFILE Arwen Pearson Guillaume Pompidor University of Hamburg European Molecular Biology Laboratory 78 PUBLICATIONS 1,083 CITATIONS 37 PUBLICATIONS 286 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Melanopsin View project AdPLA LRAT View project All content following this page was uploaded by Achim Stocker on 10 November 2017. The user has requested enhancement of the downloaded file. Article pubs.acs.org/JACS Human Cellular Retinaldehyde-Binding Protein Has Secondary Thermal 9-cis-Retinal Isomerase Activity † ‡ † § ∥ ⊥ ∇ Christin S. Bolze, , Rachel E. Helbling, Robin L. Owen, Arwen R. Pearson, Guillaume Pompidor, , ⊥ ⊥ ○ † # # Florian Dworkowski, Martin R. Fuchs, , Julien Furrer, Marcin Golczak, Krzysztof Palczewski, † † Michele Cascella,*, and Achim Stocker*, † ‡ Department of Chemistry and Biochemistry, and Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland § Diamond Light Source, Harwell Science and Innovation Campus,
    [Show full text]
  • Shedding New Light on the Generation of the Visual Chromophore PERSPECTIVE Krzysztof Palczewskia,B,C,1 and Philip D
    PERSPECTIVE Shedding new light on the generation of the visual chromophore PERSPECTIVE Krzysztof Palczewskia,b,c,1 and Philip D. Kiserb,d Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 9, 2020 (received for review May 16, 2020) The visual phototransduction cascade begins with a cis–trans photoisomerization of a retinylidene chro- mophore associated with the visual pigments of rod and cone photoreceptors. Visual opsins release their all-trans-retinal chromophore following photoactivation, which necessitates the existence of pathways that produce 11-cis-retinal for continued formation of visual pigments and sustained vision. Proteins in the retinal pigment epithelium (RPE), a cell layer adjacent to the photoreceptor outer segments, form the well- established “dark” regeneration pathway known as the classical visual cycle. This pathway is sufficient to maintain continuous rod function and support cone photoreceptors as well although its throughput has to be augmented by additional mechanism(s) to maintain pigment levels in the face of high rates of photon capture. Recent studies indicate that the classical visual cycle works together with light-dependent pro- cesses in both the RPE and neural retina to ensure adequate 11-cis-retinal production under natural illu- minances that can span ten orders of magnitude. Further elucidation of the interplay between these complementary systems is fundamental to understanding how cone-mediated vision is sustained in vivo. Here, we describe recent
    [Show full text]
  • (10) Patent No.: US 8119385 B2
    US008119385B2 (12) United States Patent (10) Patent No.: US 8,119,385 B2 Mathur et al. (45) Date of Patent: Feb. 21, 2012 (54) NUCLEICACIDS AND PROTEINS AND (52) U.S. Cl. ........................................ 435/212:530/350 METHODS FOR MAKING AND USING THEMI (58) Field of Classification Search ........................ None (75) Inventors: Eric J. Mathur, San Diego, CA (US); See application file for complete search history. Cathy Chang, San Diego, CA (US) (56) References Cited (73) Assignee: BP Corporation North America Inc., Houston, TX (US) OTHER PUBLICATIONS c Mount, Bioinformatics, Cold Spring Harbor Press, Cold Spring Har (*) Notice: Subject to any disclaimer, the term of this bor New York, 2001, pp. 382-393.* patent is extended or adjusted under 35 Spencer et al., “Whole-Genome Sequence Variation among Multiple U.S.C. 154(b) by 689 days. Isolates of Pseudomonas aeruginosa” J. Bacteriol. (2003) 185: 1316 1325. (21) Appl. No.: 11/817,403 Database Sequence GenBank Accession No. BZ569932 Dec. 17. 1-1. 2002. (22) PCT Fled: Mar. 3, 2006 Omiecinski et al., “Epoxide Hydrolase-Polymorphism and role in (86). PCT No.: PCT/US2OO6/OOT642 toxicology” Toxicol. Lett. (2000) 1.12: 365-370. S371 (c)(1), * cited by examiner (2), (4) Date: May 7, 2008 Primary Examiner — James Martinell (87) PCT Pub. No.: WO2006/096527 (74) Attorney, Agent, or Firm — Kalim S. Fuzail PCT Pub. Date: Sep. 14, 2006 (57) ABSTRACT (65) Prior Publication Data The invention provides polypeptides, including enzymes, structural proteins and binding proteins, polynucleotides US 201O/OO11456A1 Jan. 14, 2010 encoding these polypeptides, and methods of making and using these polynucleotides and polypeptides.
    [Show full text]
  • Protein Short Name
    Electronic Supplementary Material (ESI) for Nanoscale. This journal is © The Royal Society of Chemistry 2017 spot id. protein protein prot acc N° Mw unique sequence peptides identified short name full name (uniprot) peptides coverage (truncated) protein quality control & degradation (q) q1a psb3 ac. Proteasome beta 3 subunit Q9R1P1 22966 8 51% DAVSGMGVIVHVIEK - FGIQAQMVTTDFQK - FGPYYTEPVIAGLDPK - IFPMGDR - LNLYELK - LYIGLAGLATDVQTVAQR - NCVAIAADR - QIKPYTLMSMVANLLYEK q1b psb3 bas Proteasome beta 3 subunit Q9R1P1 22966 8 50% DAVSGMGVIVHVIEKDK - FGIQAQMVTTDFQK - FGPYYTEPVIAGLDPK - GKNCVAIAADR - LNLYELK - LYIGLAGLATDVQTVAQR - NCVAIAADR - QIKPYTLMSMVANLLYEKR q2a sae1 ac SUMO-activating enzyme subunit 1 Q9R1T2 38620 2 7% AQNLNPMVDVK - VSQGVEDGPEAK q2b sae1 bas SUMO-activating enzyme subunit 1 Q9R1T2 38620 16 60% AQNLNPMVDVK - DPPHNNFFFFDGMK - EALEVDWSGEK - EEAGGGGGGGISEEEAAQYDR - FDAVCLTCCSR - FFTGDVFGYHGYTFANLGEHEFVEEK - GLTMLDHEQVSPEDPGAQFLIQTGSVGR - GSGIVECLGPQ - KPESFFTK - LDSSETTMVK - NDVFDSLGISPDLLPDDFVR - NRAEASLER - TAPDYFLLQVLLK - VDTEDVEKKPESFFTK - VEKEEAGGGGGGGISEEEAAQYDR - VLFCPVKEALEVDWSGEK q3 psd13 Proteasome regulatory subunit 13 Q9WVJ2 42810 18 57% CAWGQQPDLAANEAQLLR - DLPVSEQQER - DVPAFLQQSQSSGPGQAAVWHR - ETIEDVEEMLNNLPGVTSVHSR - FLGCVDIK - GSIDEVDKR - LEELYTK - LEELYTKK - LELWCTDVK - LNIGDLQATK - LYENFISEFEHR - QLTFEEIAK - QMTDPNVALTFLEK - QWLIDTLYAFNSGAVDR - SMEMLVEHQAQDILT - VHMTWVQPR - VLDLQQIK - YYQTIGNHASYYK q4 brcc3 Lys63-deubiquitinase brcc36 P46737 36151 3 13% FTYTGTEMR - VCLESAVELPK - VEISPEQLSAASTEAER q5 ube2n Ubiquitin
    [Show full text]
  • Table Continues on Reverse Paired Immunoglobulin-Like Type 2 Receptor Beta (PILRB) Q9UKJ0 Sialic Acid-Binding Ig-Like Lectin 7 (SIGLEC7) Q9Y286
    Adenosylhomocysteinase (AHCY) P23526 DNA-(apurinic or apyrimidinic site) lyase (APEX1) P27695 Adhesion G protein-coupled receptor E2 (ADGRE2) Q9UHX3 Ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) O75356 Adhesion G-protein coupled receptor G2 (ADGRG2) Q8IZP9 Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 Q6UWV6 (ENPP7) Amyloid-like protein 1 (APLP1) P51693 Eosinophil cationic protein (RNASE3) P12724 Angiopoietin-2 (ANGPT2) O15123 Fc receptor-like protein 1 (FCRL1) Q96LA6 Angiopoietin-related protein 1 (ANGPTL1) O95841 Fructose-1,6-bisphosphatase 1 (FBP1) P09467 Angiopoietin-related protein 7 (ANGPTL7) O43827 Galanin peptides (GAL) P22466 Annexin A4 (ANXA4) P09525 Gamma-enolase (ENO2) P09104 Annexin A11 (ANXA11) P50995 Glutaredoxin-1 (GLRX) P35754 Appetite-regulating hormone (GHRL) Q9UBU3 GRB2-related adapter protein 2 (GRAP2) O75791 Arginase-1 (ARG1) P05089 Hepatoma-derived growth factor (HDGF) P51858 Aromatic-L-amino-acid decarboxylase (DDC) P20711 Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1) Q01973 B-cell antigen receptor complex-associated protein beta chain (CD79B) P40259 Insulin-like growth factor-binding protein-like 1 (IGFBPL1) Q8WX77 Cadherin-2 (CDH2) P19022 Integrin beta-7 (ITGB7) P26010 Cadherin-related family member 5 (CDHR5) Q9HBB8 Kallikrein-10 (KLK10) O43240 Calsyntenin-2 (CLSTN2) Q9H4D0 Kynurenine-oxoglutarate transaminase 1 (KYAT1) Q16773 Carbonic anhydrase 13 (CA13) Q8N1Q1 Large proline-rich protein BAG6 (BAG6) P46379 Catechol O-methyltransferase (COMT) P21964 Leucine-rich
    [Show full text]
  • O O2 Enzymes Available from Sigma Enzymes Available from Sigma
    COO 2.7.1.15 Ribokinase OXIDOREDUCTASES CONH2 COO 2.7.1.16 Ribulokinase 1.1.1.1 Alcohol dehydrogenase BLOOD GROUP + O O + O O 1.1.1.3 Homoserine dehydrogenase HYALURONIC ACID DERMATAN ALGINATES O-ANTIGENS STARCH GLYCOGEN CH COO N COO 2.7.1.17 Xylulokinase P GLYCOPROTEINS SUBSTANCES 2 OH N + COO 1.1.1.8 Glycerol-3-phosphate dehydrogenase Ribose -O - P - O - P - O- Adenosine(P) Ribose - O - P - O - P - O -Adenosine NICOTINATE 2.7.1.19 Phosphoribulokinase GANGLIOSIDES PEPTIDO- CH OH CH OH N 1 + COO 1.1.1.9 D-Xylulose reductase 2 2 NH .2.1 2.7.1.24 Dephospho-CoA kinase O CHITIN CHONDROITIN PECTIN INULIN CELLULOSE O O NH O O O O Ribose- P 2.4 N N RP 1.1.1.10 l-Xylulose reductase MUCINS GLYCAN 6.3.5.1 2.7.7.18 2.7.1.25 Adenylylsulfate kinase CH2OH HO Indoleacetate Indoxyl + 1.1.1.14 l-Iditol dehydrogenase L O O O Desamino-NAD Nicotinate- Quinolinate- A 2.7.1.28 Triokinase O O 1.1.1.132 HO (Auxin) NAD(P) 6.3.1.5 2.4.2.19 1.1.1.19 Glucuronate reductase CHOH - 2.4.1.68 CH3 OH OH OH nucleotide 2.7.1.30 Glycerol kinase Y - COO nucleotide 2.7.1.31 Glycerate kinase 1.1.1.21 Aldehyde reductase AcNH CHOH COO 6.3.2.7-10 2.4.1.69 O 1.2.3.7 2.4.2.19 R OPPT OH OH + 1.1.1.22 UDPglucose dehydrogenase 2.4.99.7 HO O OPPU HO 2.7.1.32 Choline kinase S CH2OH 6.3.2.13 OH OPPU CH HO CH2CH(NH3)COO HO CH CH NH HO CH2CH2NHCOCH3 CH O CH CH NHCOCH COO 1.1.1.23 Histidinol dehydrogenase OPC 2.4.1.17 3 2.4.1.29 CH CHO 2 2 2 3 2 2 3 O 2.7.1.33 Pantothenate kinase CH3CH NHAC OH OH OH LACTOSE 2 COO 1.1.1.25 Shikimate dehydrogenase A HO HO OPPG CH OH 2.7.1.34 Pantetheine kinase UDP- TDP-Rhamnose 2 NH NH NH NH N M 2.7.1.36 Mevalonate kinase 1.1.1.27 Lactate dehydrogenase HO COO- GDP- 2.4.1.21 O NH NH 4.1.1.28 2.3.1.5 2.1.1.4 1.1.1.29 Glycerate dehydrogenase C UDP-N-Ac-Muramate Iduronate OH 2.4.1.1 2.4.1.11 HO 5-Hydroxy- 5-Hydroxytryptamine N-Acetyl-serotonin N-Acetyl-5-O-methyl-serotonin Quinolinate 2.7.1.39 Homoserine kinase Mannuronate CH3 etc.
    [Show full text]
  • 16118909.Pdf
    PDF hosted at the Radboud Repository of the Radboud University Nijmegen This full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/30002 Please be advised that this information was generated on 2014-11-20 and may be subject to change. of Sharola Dharmaraj amaurosis analysis and congenital Clinical molecular Leber Clinical and molecular analysis of Leber congenital amaurosis Sharola Dharmaraj Clinical and molecular analysis of Leber congenital amaurosis Sharola Dharmaraj SSharolaharola BBW.inddW.indd 1 229-May-079-May-07 110:45:200:45:20 AAMM Clinical and molecular analysis of Leber congenital amaurosis PhD thesis Radboud University Nijmegen Medical Centre Sharola Dharmaraj ISBN: 978-90-9021-989-9 © 2007 S. Dharmaraj All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, by print or otherwise, without permission in writing from the author. Cover image: Fundus in LCA5-associated LCA (K.Klima) Print and layout by: Optima Grafi sche Communicatie, Rotterdam SSharolaharola BBW.inddW.indd 2 229-May-079-May-07 110:45:220:45:22 AAMM Clinical and molecular analysis of Leber congenital amaurosis Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnifi cus prof. mr. S.C.J.J Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 2 juli 2007 om 13.30 uur precies door Sharola Dharmaraj geboren op 11 december 1961 te India SSharolaharola BBW.inddW.indd 3 229-May-079-May-07 110:45:220:45:22 AAMM Promotor: Prof.
    [Show full text]
  • Mechanism‐Guided Design and Synthesis of a Mitochondria
    Author Manuscript Title: Mechanism-Guided Design and Synthesis of Mitochondria-targeting Artemisi- nin Analog with Enhanced Anticancer Activity Authors: Chong-Jing Zhang, Ph.D.; Jigang Wang; Jianbin Zhang; Yew Mun Lee; Guangxue Feng; Teck Kwang Lim; Han Ming Shen; Qingsong Lin; Bin Liu This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofrea- ding process, which may lead to differences between this version and the Version of Record. To be cited as: 10.1002/anie.201607303 Link to VoR: http://dx.doi.org/10.1002/anie.201607303 COMMUNICATION Mechanism-Guided Design and Synthesis of Mitochondria- targeting Artemisinin Analog with Enhanced Anticancer Activity Chong-Jing Zhang,#[a] Jigang Wang,#*[b,c] Jianbin Zhang,[d] Yew Mun Lee,[c] Guangxue Feng,[a] Teck Kwang Lim,[c] Han-Ming Shen,[d] Qingsong Lin,*[c] and Bin Liu*[a][e] Abstract: Understanding the mechanism of action (MOA) of However, there remain debates over the exact mechanism of bioactive natural products will guide the endeavor to improve their endoperoxide bridge activation in vivo.[16] Both free ferrous cellular activities. Artemisinin and its derivatives are reported to iron[17,18] and heme[19] have been proposed to be ART inhibit cancer cell proliferation, yet with much lower efficiencies than activators.[20] Very recently, we used a chemical proteomics their roles in killing malaria parasites. To improve their efficacies on approach to show that, heme, rather than free ferrous iron, cancer cells, we firstly studied the MOA of artemisinin using directly activates ART in malaria parasites, which then chemical proteomics and found that free heme could directly promiscuously targets various proteins within the parasites.[21] activate artemisinin.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur Et Al
    US 20150240226A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur et al. (43) Pub. Date: Aug. 27, 2015 (54) NUCLEICACIDS AND PROTEINS AND CI2N 9/16 (2006.01) METHODS FOR MAKING AND USING THEMI CI2N 9/02 (2006.01) CI2N 9/78 (2006.01) (71) Applicant: BP Corporation North America Inc., CI2N 9/12 (2006.01) Naperville, IL (US) CI2N 9/24 (2006.01) CI2O 1/02 (2006.01) (72) Inventors: Eric J. Mathur, San Diego, CA (US); CI2N 9/42 (2006.01) Cathy Chang, San Marcos, CA (US) (52) U.S. Cl. CPC. CI2N 9/88 (2013.01); C12O 1/02 (2013.01); (21) Appl. No.: 14/630,006 CI2O I/04 (2013.01): CI2N 9/80 (2013.01); CI2N 9/241.1 (2013.01); C12N 9/0065 (22) Filed: Feb. 24, 2015 (2013.01); C12N 9/2437 (2013.01); C12N 9/14 Related U.S. Application Data (2013.01); C12N 9/16 (2013.01); C12N 9/0061 (2013.01); C12N 9/78 (2013.01); C12N 9/0071 (62) Division of application No. 13/400,365, filed on Feb. (2013.01); C12N 9/1241 (2013.01): CI2N 20, 2012, now Pat. No. 8,962,800, which is a division 9/2482 (2013.01); C07K 2/00 (2013.01); C12Y of application No. 1 1/817,403, filed on May 7, 2008, 305/01004 (2013.01); C12Y 1 1 1/01016 now Pat. No. 8,119,385, filed as application No. PCT/ (2013.01); C12Y302/01004 (2013.01); C12Y US2006/007642 on Mar. 3, 2006.
    [Show full text]
  • WO 2017/187183 Al 02 November 2017 (02.11.2017) W!P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/187183 Al 02 November 2017 (02.11.2017) W!P O PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 39/00 (2006.01) C07K 16/28 (2006.01) kind of national protection available): AE, AG, AL, AM, C07K 14/78 (2006.01) G01N 33/74 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/GB2017/05 1188 HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 27 April 2017 (27.04.2017) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/328,355 27 April 2016 (27.04.2016) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (71) Applicant: ITARA THERAPEUTICS [GB/GB]; UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 158-160 North Gower Street, London NW1 2ND (GB).
    [Show full text]
  • Proteomic Landscape of the Human Choroid–Retinal Pigment Epithelial Complex
    Supplementary Online Content Skeie JM, Mahajan VB. Proteomic landscape of the human choroid–retinal pigment epithelial complex. JAMA Ophthalmol. Published online July 24, 2014. doi:10.1001/jamaophthalmol.2014.2065. eFigure 1. Choroid–retinal pigment epithelial (RPE) proteomic analysis pipeline. eFigure 2. Gene ontology (GO) distributions and pathway analysis of human choroid– retinal pigment epithelial (RPE) protein show tissue similarity. eMethods. Tissue collection, mass spectrometry, and analysis. eTable 1. Complete table of proteins identified in the human choroid‐RPE using LC‐ MS/MS. eTable 2. Top 50 signaling pathways in the human choroid‐RPE using MetaCore. eTable 3. Top 50 differentially expressed signaling pathways in the human choroid‐RPE using MetaCore. eTable 4. Differentially expressed proteins in the fovea, macula, and periphery of the human choroid‐RPE. eTable 5. Differentially expressed transcription proteins were identified in foveal, macular, and peripheral choroid‐RPE (p<0.05). eTable 6. Complement proteins identified in the human choroid‐RPE. eTable 7. Proteins associated with age related macular degeneration (AMD). This supplementary material has been provided by the authors to give readers additional information about their work. © 2014 American Medical Association. All rights reserved. 1 Downloaded From: https://jamanetwork.com/ on 09/25/2021 eFigure 1. Choroid–retinal pigment epithelial (RPE) proteomic analysis pipeline. A. The human choroid‐RPE was dissected into fovea, macula, and periphery samples. B. Fractions of proteins were isolated and digested. C. The peptide fragments were analyzed using multi‐dimensional LC‐MS/MS. D. X!Hunter, X!!Tandem, and OMSSA were used for peptide fragment identification. E. Proteins were further analyzed using bioinformatics.
    [Show full text]
  • Human Cone Photoreceptor Dependence on RPE65 Isomerase
    Human cone photoreceptor dependence on RPE65 isomerase Samuel G. Jacobson*†, Tomas S. Aleman*, Artur V. Cideciyan*, Elise Heon‡, Marcin Golczak§, William A. Beltran¶, Alexander Sumaroka*, Sharon B. Schwartz*, Alejandro J. Roman*, Elizabeth A. M. Windsor*, James M. Wilsonʈ, Gustavo D. Aguirre¶, Edwin M. Stone**, and Krzysztof Palczewski†§ *Scheie Eye Institute, Department of Ophthalmology, School of Medicine, ¶Section of Ophthalmology, School of Veterinary Medicine, and ʈDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; ‡Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada M56 1X8; §Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106; and **Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 3, 2007 (received for review July 6, 2007) The visual (retinoid) cycle, the enzymatic pathway that regenerates and mammals, including mouse, rabbit, and cow (12); both short- chromophore after light absorption, is located primarily in the retinal wavelength (SW) and long-wavelength (LW) murine cones were pigment epithelium (RPE) and is essential for rod photoreceptor RPE65-positive. At variance, however, are other reports that failed survival. Whether this pathway also is essential for cone photorecep- to identify RPE65 immunoreactivity in cone photoreceptors of cow, tor survival is unknown, and there are no data from man or monkey rat, chicken, frog, NrlϪ/Ϫ mice (11, 13), dogs (14), and human to address this question. The visual cycle is naturally disrupted in extrafoveal retina (13). humans with Leber congenital amaurosis (LCA), which is caused by To gain insight into human cone visual pigment regeneration, we mutations in RPE65, the gene that encodes the retinoid isomerase.
    [Show full text]