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Dissection of the molecular pathology of Usher syndrome Erwin van Wijk Erwin van Wijk, 2009 Dissection of the molecular pathology of Usher syndrome Publication of this thesis was financially supported by the Departments of Otorhinolaryngology and Human Genetics, Radboud University Nijmegen Medical Centre; Atos Medical BV; Bayer HealthCare; Carl Zeiss BV; GlaxoSmithKline BV; EmiD audiologische apparatuur; Veenhuis Medical Audio BV; Eurogentec BV; IKS; Artu Biologicals; Schoonenberg Hoorcomfort; Beter Horen BV; Roche Diagnostics Nederland BV. © 2009, Erwin van Wijk, Nijmegen, The Netherlands Cover design: Krijn Ontwerp, Nijmegen Layout: Erwin van Wijk Printed by: Print Partners Ipskamp, Enschede ISBN: 978-90-9024062-6 Dissection of the molecular pathology of Usher syndrome 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 Magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op vrijdag 29 mei 2009 om 10.30 uur precies door Hendrikus Antonius Rudolfus van Wijk geboren op 22 maart 1975 te Horssen Promotores: Prof. dr. C.W.R.J. Cremers Prof. dr. F.P.M. Cremers Co-promotores: Dr. H. Kremer Dr. R. Roepman Manuscriptcommissie: Prof. dr. J. Schalkwijk (voorzitter) Prof. dr. K. Avraham (Tel Aviv, Israel) Dr. W.J.A.J. Hendriks Table of contents Abbreviations................................................................................................. 7 Chapter 1 : General introduction 1. History of Usher syndrome................................................................... 11 2. The ear............................................................................................... 11 2.1 Development and structure of the cochlea………………………..…… 12 2.2 Sound perception……………………………………………………… 14 2.3 Vestibular system……………………………………………………... 15 3. The eye.............................................................................................. 16 3.1 Development and structure of the retina........................................... 16 3.2 The visual cycle............................................................................. 18 4. Clinical types and evaluation of the Usher syndrome.............................. 19 4.1 Usher syndrome type I.................................................................... 19 4.1.1 Hearing and vestibular impairment........................................ 19 4.1.2 Visual impairment............................................................... 20 4.2 Usher syndrome type II................................................................... 21 4.2.1 Hearing and vestibular impairment........................................ 21 4.2.2 Visual impairment............................................................... 21 4.3 Usher syndrome type III.................................................................. 21 4.3.1 Hearing and vestibular impairment........................................ 21 4.3.2 Visual impairment............................................................... 21 5. Prevalence of Usher syndrome.............................................................. 22 6. Genes and proteins involved in Usher syndrome..................................... 22 6.1 Loci, genes and proteins involved in USH1....................................... 23 6.1.1 USH1b/MYO7A (myosin VIIa)............................................. 23 6.1.2 USH1c/USH1C (harmonin).................................................. 24 6.1.3 USH1d/CDH23 (cadherin 23)............................................... 25 6.1.4 USH1e................................................................................ 26 6.1.5 USH1f/PCDH15 (protocadherin 15)...................................... 26 6.1.6 USH1g/USH1G (SANS)....................................................... 28 6.1.7 USH1h................................................................................ 30 6.2 Loci, genes and proteins involved in USH2....................................... 30 6.2.1 USH2a/USH2A (USH2A/usherin).......................................... 30 6.2.2 USH2c/VLGR1/GPR98 (GPR98)........................................... 31 6.2.3 USH2d/DFNB31 (whirlin).................................................... 32 6.3 Loci, genes and proteins involved in USH3....................................... 34 6.3.1 USH3a/USH3A (clarin-1)..................................................... 34 6.3.2 USH3b............................................................................... 34 7. Outline of this thesis............................................................................ 35 8. References.......................................................................................... 37 Chapter 2 Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II................................................................................. 51 Chapter 3 Scaffold protein harmonin (USH1c) provides molecular links between Usher syndrome type 1 and type 2................................................................................ 67 Chapter 4 The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.................... 91 Chapter 5 MPP1 links the Usher protein network and the Crumbs protein complex in the retina.. 119 Chapter 6 Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein............................................. 143 Chapter 7 The centrosomal ninein-like protein interacts with MKKS/BBS6 and plays a role in ciliogenesis and early embryonic development...................................... 177 Chapter 8: General discussion 1. The expanding Usher protein network......................................................... 213 2. Biological relevance of the Usher protein complex..................................... 213 3. Dynamics of the Usher protein complex...................................................... 215 4. Function of the Usher protein complex........................................................ 218 4.1 Stereocilia formation and elongation..................................................... 218 4.2 Fibrous links in the inner ear and retina................................................. 218 4.3 Planar cell polarity.................................................................................. 218 4.4 Vesicle docking and transport................................................................ 219 4.5 Synapse formation and synaptic transmission........................................ 220 4.6 Apico-basal polarity............................................................................... 220 5. Linking diseases: LCA, RP, USH, BBS, non-syndromic deafness............. 221 6. Involvement of the novel members of the protein network in disease........ 222 7. Future prospects and directions................................................................... 223 8. References................................................................................................... 225 Summary/Samenvatting.................................................................................. 231 Dankwoord………………………………………………………………………….. 239 List of publications………………………………………………………………... 245 Curriculum vitae……………………………………………………………………. 251 Appendix: colour atlas.................................................................................... 255 Abbreviations a.a. : amino acid ALA : ankle link antigen ANK : ankyrin arRP : autosomal recessive retinitis pigmentosa BB : basal body BBS : Bardet-Biedl syndrome Calx : Ca2+-binding calcium exchanger β CASK : calcium/calmodulin-dependent serine protein kinase CC : connecting cilium CDH23 : cadherin 23 CIP-98 : CASK interacting protein 98 kDa cM : centimorgan CNS : central nervous system DIG : digoxigenin DTT : 1,4-dithiothreitol eCFP : enhanced cyan fluorescent protein EGF : epidermal growth factor EM : electronmicroscopy ERG : electroretinography ESTs : expressed sequence tags FN3 : fibronectin type III GPR98 : G-protein coupled receptor 98 kDa GST : glutathion-S-transferase HA : hemagglutinin Hz : Hertz IHC : inner hair cell INL : inner nuclear layer IPL : inner plexiform layer IS : inner segment ISH : in situ hybridization kDa : kilodalton LamG : laminin G-like LamNT : laminin N-terminal LCA : Leber congenital amaurosis MAGUK : membrane-associated guanylate kinase MPP : membrane palmitoylated protein mRFP : monomeric red fluorescent protein MRI : magnetic resonance imaging MYO7A : myosin VIIa MYO15A : myosin XVa NBC3 : sodium bicarbonate transporter 3 Ngl-1 : netrin-G1 ligand Nlp : Ninein-like protein NLS : nuclear localisation signal NMDA : N-methyl-D-aspartate receptor OHC : outer hair cell OKR : optokinetic response 7 OLM : outer limiting membrane ONL : outer nuclear layer OPL : outer plexiform layer OS : outer segment PBM : PDZ-binding motif PBS : phosphate buffered saline PCDH15 : protocadherin 15 PDE : phosphodiesterase PDZ