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