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Edinburgh Research Explorer Edinburgh Research Explorer TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23) Citation for published version: Stephen, LA, Tawamie, H, Davis, GM, Tebbe, L, Nürnberg, P, Nürnberg, G, Thiele, H, Thoenes, M, Boltshauser, E, Uebe, S, Rompel, O, Reis, A, Ekici, AB, McTeir, L, Fraser, AM, Hall, E, Mill, P, Daudet, N, Cross, C, Wolfrum, U, Jamra, RA, Davey, MG & Bolz, HJ 2015, 'TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)' eLIFE, vol. 4, no. September. DOI: 10.7554/eLife.08077 Digital Object Identifier (DOI): 10.7554/eLife.08077 Link: Link to publication record in Edinburgh Research Explorer Document Version: Peer reviewed version Published In: eLIFE Publisher Rights Statement: Available under Open Access General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 05. Apr. 2019 ACCEPTED MANUSCRIPT TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome ( JBTS23) Louise A Stephen, Hasan Tawamie, Gemma M Davis, Lars Tebbe, Peter Nürnberg, Gudrun Nürnberg, Holger Thiele, Michaela Thoenes, Eugen Boltshauser, Steffen Uebe, Oliver Rompel, André Reis, Arif B Ekici, Lynn McTeir, Amy M Fraser, Emma A Hall, Pleasantine Mill, Nicolas Daudet, Courtney Cross, Uwe Wolfrum, Rami Abou Jamra, Megan G Davey, Hanno J Bolz DOI: http://dx.doi.org/10.7554/eLife.08077 Cite as: eLife 2015;10.7554/eLife.08077 Received: 13 April 2015 Accepted: 19 September 2015 Published: 19 September 2015 This PDF is the version of the article that was accepted for publication after peer review. Fully formatted HTML, PDF, and XML versions will be made available after technical processing, editing, and proofing. Stay current on the latest in life science and biomedical research from eLife. Sign up for alerts at elife.elifesciences.org 1 TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is 2 mutated in Joubert syndrome (JBTS23) 3 4 Louise A. Stephen1, Hasan Tawamie2, Gemma M. Davis1, Lars Tebbe3, Peter Nürnberg4,5, 5 Gudrun Nürnberg4, Holger Thiele4, Michaela Thoenes6, Eugen Boltshauser7, Steffen Uebe2, 6 Oliver Rompel8, André Reis2, Arif B Ekici2, Lynn McTeir1, Amy M. Fraser1, Emma A. Hall9, 7 Pleasantine Mill9, Nicolas Daudet10, Courtney Cross11, Uwe Wolfrum3, Rami Abou 8 Jamra2,12,13*, Megan G. Davey1*+, Hanno J. Bolz6,14*+ 9 10 1Division of Developmental Biology, The Roslin Institute and R(D)SVS, University of Edinburgh, 11 Easter Bush, Midlothian, UK EH25 9RG 12 2Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 13 Germany 14 3Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University (JGU) of Mainz, 15 Germany 16 4Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), 17 University of Cologne, Germany 18 5Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 19 University of Cologne, Germany 20 6Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany 21 7Department of Paediatric Neurology, University Children’s Hospital of Zurich, Zurich, Switzerland 22 8Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany 23 9MRC Human Genetics Unit MRC IGMM, University of Edinburgh, UK 24 10UCL Ear Institute, London WC1X 8EE, UK 25 11A.T Still University, School of Osteopathic Medicine, 5850 E. Still Circle, Mesa, Arizona, 85206 26 12Centogene AG, Rostock, Germany 27 13Institute of Human Genetics, University Medical Center Leipzig, Leipzig 28 14Bioscientia Center for Human Genetics, Ingelheim, Germany 29 30 * equal senior authors 31 + Corresponding authors: [email protected]; [email protected] 32 33 Short title: KIAA0586 (TALPID3) is mutated in Joubert syndrome 1 34 Key words: Joubert syndrome, intellectual disability, TALPID3, KIAA0586, cilia, ciliopathy, 35 centrosome, cell polarity, centriolar satellites 36 2 37 ABSTRACT 38 Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can 39 affect several organ systems. Mutations in known JBTS genes account for approximately half 40 of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel 41 locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a 42 known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were 43 identified in two additional JBTS patients. One mutation, c.428delG (p.Arg143Lysfs*4), is 44 unexpectedly common in the general population, and may be a major contributor to JBTS. 45 We demonstrate KIAA0586 protein localization at the basal body in human and mouse 46 photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We 47 show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue 48 polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS 49 and other ciliopathies may in part result from cell polarity defects. 50 3 51 INTRODUCTION 52 Joubert syndrome (JBTS) is a rare ciliopathy characterized by a specific midhindbrain 53 malformation presenting as ‘molar tooth sign’ on axial MRI. Patients typically have a 54 perturbed respiratory pattern in the neonatal period and pronounced psychomotor delay. 55 Depending on the genetic subtype, there may be additional retinal degeneration, 56 nephronophthisis, liver fibrosis and skeletal abnormalities (such as polydactyly). JBTS is 57 genetically heterogeneous, with recessive mutations reported in more than 20 genes encoding 58 proteins related to the function of cilia and associated structures (1, 2). 59 Cilia are axoneme-based organelles which protrude into the extracellular milieu, anchored to 60 the cell by a modified centriole (basal body). They are present in virtually every cell type (3). 61 Non-motile ‘primary’ cilia play essential roles in mechanotransduction, chemosensation and 62 intracellular signal transduction, including Hedgehog (Hh), PDGFα and WNT pathways, in 63 embryonic development and adult tissue homeostasis (4). In addition, highly modified and 64 specialized cilia constitute the light-sensitive outer segments of retinal photoreceptor cells. 65 Dysfunction of cilia, centrioles of basal bodies and centrosomes can lead to a spectrum of 66 developmental single- or multi-organ disorders termed "ciliopathies" (5). 67 KIAA0586 (TALPID3; MIM #610178, MIM #000979-9031) is essential for vertebrate 68 development and ciliogenesis. The KIAA0586 (TALPID3) protein is localized at the 69 centrosome in human, chicken, mouse and zebrafish cells (6-8), and in particular at the distal 70 end of the mother centriole – the basal body of cilia (9). In model organisms, KIAA0586 null 71 mutations cause failure of basal body docking and loss of cilia, leading to early embryonic 72 lethal phenotypes (6, 10-12). KIAA0586 (TALPID3) binding partners include PCM1, 73 Cep120 and CP110, which interact with a known JBTS protein, CEP290 (13). 74 Here, we report three JBTS families with loss-of-function mutations in KIAA0586. Using 75 animal models, we demonstrate that TALPID3 (KIAA0586) is not only essential for 4 76 transduction of Hedgehog signaling but plays an important role in centrosomal localization, 77 orientation and length. Finally, and beyond its established requirement for ciliogenesis, 78 TALPID3 (KIAA0586) plays a key role in cell and tissue polarity. 79 80 5 81 METHODS 82 83 Patients 84 Blood samples for DNA extraction were obtained with written informed consent. All 85 investigations were conducted according to the Declaration of Helsinki, and the study was 86 approved by the institutional review board of the Ethics Committees of the University of 87 Erlangen-Nürnberg, the University of Bonn, and the University Hospital of Cologne. 88 89 Genetic analysis of human JBTS families 90 In accordance with the Human Gene Nomenclature Committee (HGNC), we have used 91 KIAA0586/KIAA0586 for designation of the human gene and protein, respectively. In 92 accordance with the Chicken Gene Nomenclature Committee (CGNC), we use 93 TALPID3/TALPID3 for designation of the chicken gene and protein, respectively. Although 94 the current gene symbol for the mouse gene is 2700049A03Rik (protein: 2700049A03RIK), 95 we use Talpid3/Talpid3 as the gene and protein names, respectively. Where we refer to a 96 generic conclusion on the function of the orthologs of KIAA0586, we use KIAA0586. As in 97 previous publications, the chicken model is referred to as talpid3, and the mouse model is 98 referred to as Talpid3-/-. The nomenclature of human KIAA0586 mutations refers to reference 99 sequence NM_001244189.1 (corresponding protein: NP_001231118.1). The Exome 100 Aggregation Consortium (ExAC) database (Cambridge, MA, USA; 101 http://exac.broadinstitute.org), which aggregates numerous
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