title: Mutation of POC1B in a severe syndromic retinal ciliopathy.
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.
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Bodo B
authors.initials: BB
authors.lastname: Beck
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Phillips
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wegner
authors.forename: Michaela
authors.initials: M
authors.lastname: Thoenes
authors.forename: Andrea
authors.initials: A
authors.lastname: Pannes
authors.forename: Josephina
authors.initials: J
authors.lastname: Sampson
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.forename: Heike
authors.initials: H
authors.lastname: Göbel
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.forename: Antje
authors.initials: A
authors.lastname: Neugebauer
authors.forename: Andrea
authors.initials: A
authors.lastname: Hedergott
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.forename: Simon
authors.initials: S
authors.lastname: Staubach
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberger
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Lars
authors.initials: L
authors.lastname: Tebbe
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yundong
authors.initials: Y
authors.lastname: Wu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fry
authors.forename: Monte
authors.initials: M
authors.lastname: Westerfield
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000015:Abnormalities, Multiple; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002526:Cerebellar Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D007493:Iraq; D007668:Kidney / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012160:Retina / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish
chemical_list: D018797:Cell Cycle Proteins; C000592372:POC1B protein, human
keywords: Joubert syndrome; LCA; POC1B; ciliopathy; zebrafish