Mutation of POC1B in a severe syndromic retinal ciliopathy

Item Type:	Article
Title:	Mutation of POC1B in a severe syndromic retinal ciliopathy
Creators Name:	Beck, B.B. and Phillips, J.B. and Bartram, M.P. and Wegner, J. and Thoenes, M. and Pannes, A. and Sampson, J. and Heller, R. and Göbel, H. and Koerber, F. and Neugebauer, A. and Hedergott, A. and Nürnberg, G. and Nürnberg, P. and Thiele, H. and Altmüller, J. and Toliat, M.R. and Staubach, S. and Boycott, K.M. and Valente, E.M. and Janecke, A.R. and Eisenberger, T. and Bergmann, C. and Tebbe, L. and Wang, Y. and Wu, Y. and Fry, A.M. and Westerfield, M. and Wolfrum, U. and Bolz, H.J.
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.Arg106Pro(POC1B) in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106Pro(POC1B) 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.
Keywords:	POC1B, LCA, Joubert Syndrome, Ciliopathy, Zebrafish, Animals, Mice
Source:	Human Mutation
ISSN:	1059-7794
Publisher:	Wiley-Blackwell
Volume:	35
Number:	10
Page Range:	1153-1162
Date:	October 2014
Official Publication:	https://doi.org/10.1002/humu.22618
PubMed:	View item in PubMed

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