2. Academic Validation
  3. Mutation of POC1B in a severe syndromic retinal ciliopathy

Mutation of POC1B in a severe syndromic retinal ciliopathy

  • Hum Mutat. 2014 Oct;35(10):1153-62. doi: 10.1002/humu.22618.
Bodo B Beck 1,  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
Affiliations

Affiliation

  • 1 Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
PMID: 25044745 DOI: 10.1002/humu.22618
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.

Keywords

Joubert syndrome; LCA; POC1B; ciliopathy; zebrafish.

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