title: TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23).
abstract: Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.
authors.affiliation: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Louise A
authors.identifier: http://orcid.org/0000-0001-6795-0383
authors.initials: LA
authors.lastname: Stephen
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Tawamie
authors.affiliation: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Davis
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tebbe
authors.affiliation: Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Thoenes
authors.affiliation: Department of Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rompel
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lynn
authors.initials: L
authors.lastname: McTeir
authors.affiliation: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fraser
authors.affiliation: Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Hall
authors.affiliation: Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pleasantine
authors.initials: P
authors.lastname: Mill
authors.affiliation: UCL Ear Institute, University College London, London, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Daudet
authors.affiliation: School of Osteopathic Medicine, A.T. Still University, Mesa, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Cross
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.|Centogene, Rostock, Germany.|Institute of Human Genetics, Leipzig University, Leipzig, Germany.
authors.forename: Rami Abou
authors.initials: RA
authors.lastname: Jamra
authors.affiliation: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Megan G
authors.initials: MG
authors.lastname: Davey
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.|Bioscientia Center for Human Genetics, Bioscientia International Business, Ingelheim am Rhein, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D016764:Cell Polarity; D018385:Centrosome / Q000378:metabolism*; D002531:Cerebellum / Q000002:abnormalities*; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000235:genetics; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D051379:Mice; D009154:Mutation; D012160:Retina / Q000002:abnormalities*
chemical_list: D018797:Cell Cycle Proteins; C587687:KIAA0586 protein, human
keywords: Joubert syndrome; KIAA0586; Talpid3; cell polarity; centrosome; chicken; ciliopathy; developmental biology; human; human biology; medicine; mouse; stem cells