Mutation of POC1B in a Severe Syndromic Retinal Ciliopathy |
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| Authors: | Bodo B Beck Jennifer B Phillips Malte P Bartram Jeremy Wegner Michaela Thoenes Andrea Pannes Josephina Sampson Raoul Heller Heike Göbel Friederike Koerber Antje Neugebauer Andrea Hedergott Gudrun Nürnberg Peter Nürnberg Holger Thiele Janine Altmüller Mohammad R Toliat Simon Staubach Kym M Boycott Enza Maria Valente Andreas R Janecke Tobias Eisenberger Carsten Bergmann Lars Tebbe Yang Wang Yundong Wu Andrew M Fry Monte Westerfield Uwe Wolfrum Hanno J Bolz |
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| Institution: | 1. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany;2. Institute of Neuroscience, University of Oregon, Eugene, Oregon;3. Department II of Internal Medicine and Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany;4. Department of Biochemistry, University of Leicester, Leicester, United Kingdom;5. Department of Pathology, University Hospital of Cologne, Cologne, Germany;6. Department of Radiology, University Hospital of Cologne, Cologne, Germany;7. Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany;8. Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany;9. Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany;10. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada;11. Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Institute, San Giovanni Rotondo, Italy;12. Department of Medicine and Surgery, University of Salerno, Salerno, Italy;13. Department of Pediatrics I, and Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria;14. Center for Human Genetics, Bioscientia, Ingelheim, Germany;15. Department of Medicine, Renal Division, University of Freiburg Medical Center, Freiburg, Germany;16. Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany;17. Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, P.R. China;18. College of Chemistry, Peking University, Beijing, P.R. China;19. Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University of Mainz, Mainz, Germany |
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| Abstract: | We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD. |
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| Keywords: | POC1B LCA Joubert syndrome ciliopathy zebrafish |
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