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Mutation ofPOC1Bina severe syndromic retinal ciliopathy

journal contribution
posted on 22.07.2014, 14:22 by 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
We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA),Joubert syndrome (JBTS), and polycystic kidney disease. Targeted NGS 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. Insilico modeling suggested a requirement of p.Arg106for 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.Arg106Pro[subscript POC1]B in a family with non-syndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106Pro[subscript POC1]B may thus be highly variable, analogous to homozygous p.Leu710Ser inWDR19 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 polycystic kidney disease.



Human Mutation, 2014, DOI: 10.1002/humu.22618


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