Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
Hasan Tawamie
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Gemma M Davis
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
Lars Tebbe
Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany
Peter Nürnberg
Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence, University of Cologne, Cologne, Germany
Gudrun Nürnberg
Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Holger Thiele
Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Michaela Thoenes
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany
Eugen Boltshauser
Department of Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland
Steffen Uebe
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Oliver Rompel
Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
André Reis
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Arif B Ekici
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
Lynn McTeir
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
Amy M Fraser
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
Emma A Hall
Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Pleasantine Mill
Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Nicolas Daudet
UCL Ear Institute, University College London, London, United Kingdom
Courtney Cross
School of Osteopathic Medicine, A.T. Still University, Mesa, United States
Uwe Wolfrum
Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany
Rami Abou Jamra
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centogene, Rostock, Germany; Institute of Human Genetics, Leipzig University, Leipzig, Germany
Megan G Davey
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
Hanno J Bolz
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany; Bioscientia Center for Human Genetics, Bioscientia International Business, Ingelheim am Rhein, Germany
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.
