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 JBTS patients. 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.
Animal experimentation: Talpid3 chicken lines are maintained at the Roslin Institute under UK Home Office license 60/4506 [Dr Paul Hocking], after ethical review.Animal experiments carried out at the JGU Mainz corresponded to the statement by the Association for Research in Vision and Ophthalmology (ARVO) as to care and use of animals in research.
Human subjects: Blood samples for DNA extraction were obtained with written informed consent. All investigations were conducted according to the Declaration of Helsinki, and the study was approved by the institutional review board of the Ethics Committees of the University of Erlangen-N�rnberg, the University of Bonn, and the University Hospital of Cologne.
- Harry C Dietz, Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, United States
© 2015, Stephen et al.
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