期刊
HUMAN MUTATION
卷 35, 期 10, 页码 1153-1162出版社
WILEY
DOI: 10.1002/humu.22618
关键词
POC1B; LCA; Joubert syndrome; cliopathy; zebrafish
资金
- Marie-Louise Geissler-Stiftung and Imhoff-Stiftung
- Imhoff-Stiftung
- Koeln Fortune, Faculty of Medicine, University of Cologne [172/2013]
- NIH [DC004186, DC010447, 0D011195, HD22486]
- Deutsche Forschungsgemeinschaft [GRK 1044]
- FAUN-Stiftung (Nurnberg), European Community [FP7/2009/241955 (SYSCILIA)]
- BMBF [0314106]
- NSFC [21133002]
- Kidney Research UK [RP2/2013]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F010702/1]
- Biotechnology and Biological Sciences Research Council [BB/F010702/1] Funding Source: researchfish
- Kidney Research UK [RP2/2013] Funding Source: researchfish
- Worldwide Cancer Research [13-0042] Funding Source: researchfish
- BBSRC [BB/F010702/1] Funding Source: UKRI
We describe a consanguineous Iraqi family with Leber congenital arnaurosis (LCA), Jouber syndrome (JBTS), and polycystic kidney disease (PI(I)). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous misnse 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.Arg106Pro(POCIB) for the formation of the third WI)40 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 Poclb in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photor p or connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes hotnozygosfor p.Arg106PrnPociB in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106Propocth may thus be highly variable, analogous to homozygous p.Lett710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal ingrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.
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