TY - JOUR
T1 - Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy
AU - Roosing, Susanne
AU - Lamers, Ideke J C
AU - de Vrieze, Erik
AU - van den Born, L Ingeborgh
AU - Lambertus, Stanley
AU - Arts, Heleen H
AU - Peters, Theo A
AU - Hoyng, Carel B
AU - Kremer, Hannie
AU - Hetterschijt, Lisette
AU - Letteboer, Stef J F
AU - van Wijk, Erwin
AU - Roepman, Ronald
AU - den Hollander, Anneke I
AU - Cremers, Frans P M
N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2014/8/7
Y1 - 2014/8/7
N2 - Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors.
AB - Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors.
KW - Amino Acid Sequence
KW - Animals
KW - Basal Bodies
KW - Base Sequence
KW - Cell Cycle Proteins/genetics
KW - Cells, Cultured
KW - Exome/genetics
KW - Eye Proteins/genetics
KW - Female
KW - Gene Knockdown Techniques
KW - HEK293 Cells
KW - Humans
KW - Male
KW - Molecular Sequence Data
KW - Morpholinos/genetics
KW - Mutation, Missense
KW - Netherlands
KW - Photoreceptor Connecting Cilium/metabolism
KW - Retinal Cone Photoreceptor Cells/pathology
KW - Retinal Photoreceptor Cell Outer Segment/physiology
KW - Retinal Pigment Epithelium/metabolism
KW - Retinal Rod Photoreceptor Cells/pathology
KW - Retinitis Pigmentosa/genetics
KW - Sequence Analysis, DNA
KW - Turkey
KW - Vision Disorders/genetics
KW - Zebrafish
U2 - 10.1016/j.ajhg.2014.06.012
DO - 10.1016/j.ajhg.2014.06.012
M3 - Article
C2 - 25018096
SN - 0002-9297
VL - 95
SP - 131
EP - 142
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -