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Elife. 2015 Sep 19;4. pii: e08077. doi: 10.7554/eLife.08077.

TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23).

Author information

1
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
2
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
3
Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
4
Cologne Center for Genomics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
5
Cologne Cluster of Excellence, University of Cologne, Cologne, Germany.
6
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
7
Department of Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
8
Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9
Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
10
UCL Ear Institute, University College London, London, United Kingdom.
11
School of Osteopathic Medicine, A.T. Still University, Mesa, United States.
12
Centogene, Rostock, Germany.
13
Institute of Human Genetics, Leipzig University, Leipzig, Germany.
14
Bioscientia Center for Human Genetics, Bioscientia International Business, Ingelheim am Rhein, Germany.

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.

KEYWORDS:

Joubert syndrome; KIAA0586; Talpid3; cell polarity; centrosome; chicken; ciliopathy; developmental biology; human; human biology; medicine; mouse; stem cells

PMID:
26386247
PMCID:
PMC4641851
DOI:
10.7554/eLife.08077
[Indexed for MEDLINE]
Free PMC Article

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