Alternative titles; symbols
HGNC Approved Gene Symbol: POC1B
Cytogenetic location: 12q21.33 Genomic coordinates (GRCh38) : 12:89,401,467-89,526,047 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.33 | Cone-rod dystrophy 20 | 615973 | Autosomal recessive | 3 |
POC1A (614783) and POC1B localize to centrioles and related structures and appear to play roles in centriole duplication and/or maintenance (Keller et al., 2009).
By searching a human database for sequences similar to Xenopus Pix1, Hames et al. (2008) identified POC1B, which they called PIX1, and obtained the full-length cDNA clone. The deduced 478-amino acid PIX1 protein contains an N-terminal WD40 domain predicted to fold into a 7-bladed beta propeller and a C-terminal coiled-coil domain. In Xenopus, RT-PCR detected high expression of Pix1 in ovary, weaker expression in testis, and very low expression in other tissues. Variable PIX1 expression was detected in all human cell lines examined. Hames et al. (2008) also identified Xenopus and human PIX2 (POC1A) and 1 or 2 PIX orthologs in rodents, zebrafish, Drosophila, and amphioxus, but not in C. elegans or yeast. Immunohistochemical analysis detected Xenopus Pix1 in the single large mitochondrial cloud of previtellogenic oocytes. Using an antibody that did not differentiate between human PIX proteins for immunohistochemical analysis, Hames et al. (2008) found that PIX associated with mitochondria, centrioles, and basal bodies in human cell lines. Immunoelectron microscopic analysis of human RPE1 retinal pigment epithelial cells revealed that PIX mostly associated with the central region and distal end of the centriole barrel, with concentration within the lumen. Epitope-tagged PIX1 and PIX2 were expressed in overlapping but distinct patterns in mitochondria, centrosome, basal body, and spindle microtubules during the cell cycle in transfected U2OS cells. Western blot analysis of several human cell lines detected PIX1 at an apparent molecular mass of about 54 kD.
Keller et al. (2009) found that fluorescence-tagged POC1A and POC1B localized to both mother centrioles and newly forming daughter centrioles in transfected HeLa and U2OS cells, a pattern of expression that was also observed for Chlamydomonas Poc1.
Using POC1B antibodies, Beck et al. (2014) analyzed POC1B distribution in the human and mouse retina. In both, POC1B was detected predominantly in the ciliary region of photoreceptor cells and synapses of the outer plexiform layer. Immunofluorescence analysis revealed POC1B localization in the periciliary region at the basal body and the adjacent centriole of the photoreceptor cilium.
Keller et al. (2009) stated that all organisms with standard triplet microtubule-containing centrioles in at least part of their life cycle have a POC1 gene. In vertebrates, the POC1 gene is duplicated.
Hames et al. (2008) stated that the human POC1B gene maps to chromosome 12q21.33.
Hames et al. (2008) found that epitope-tagged PIX2, and more weakly PIX1, associated with microtubules in transfected HeLa cells. Inhibition of PIX protein function via interfering antibodies disrupted cell division in U2OS cells, resulting in a high proportion of cells that were multinucleated or remained connected by a thin cytoplasmic bridge.
Keller et al. (2009) found that overexpression of fluorescence-tagged POC1B in U2OS cells resulted in duplication of centrioles, which was countered by small interfering RNA directed against POC1B or against both POC1A and POC1B. Overexpression of POC1B also increased centriole length in a significant proportion of transfected cells.
In 3 Turkish sibs and a Dutch man with cone-rod dystrophy (CORD20; 615973), Roosing et al. (2014) identified homozygosity or compound heterozygosity for mutations in the POC1B gene (614784.0001-614784.0003, respectively). The mutations, which segregated with disease in both families, were not found in controls. All 3 variants were located within the N-terminal WD40 domain. In functional analyses, the mutants showed loss of localization to the basal body of the primary cilium as well as loss of interaction with FAM161A (613596).
In affected members of a consanguineous Turkish family segregating autosomal recessive CORD mapping to chromosome 12q21.33, Durlu et al. (2014) independently identified homozygosity for a missense mutation (R106P; 614784.0001) in the POC1B gene that segregated with disease and was not found in controls.
Using poc1b-specific antisense morpholino oligonucleotides in zebrafish embryos, Roosing et al. (2014) generated poc1b morphants and observed the same ciliopathy phenotypes as previously reported (Pearson et al., 2009), including smaller eyes, curved body axis, pigment mislocalization, and pericardial edema, without higher mortality than controls. Optokinetic responses were absent or lower in morphants with small eyes than wildtype larvae; histologic analysis showed shortened or absent outer segments of the photoreceptors, with normal lamination. Immunohistochemical staining for typical rod and cone markers revealed that immunoreactivity was absent in some parts of the morphant retina, although the nuclei of the photoreceptor cells were still present. Injection of wildtype POC1B mRNA rescued the poc1b knockdown phenotype, but injection with R106P (614784.0001) or Gln67del (614784.0002) mutant POC1B mRNA did not.
Beck et al. (2014) performed poc1b knockdown in zebrafish and observed cystic kidneys and retinal degeneration with shortened as well as reduced numbers of photoreceptor-connecting cilia, consistent with human syndromic ciliopathy.
In 3 Turkish sibs with cone dystrophy or cone-rod dystrophy (CORD20; 615973), Roosing et al. (2014) identified homozygosity for a c.317G-C transversion in the POC1B gene, resulting in an arg106-to-pro (R106P) substitution at a highly conserved residue within the WD40 domain. The mutation, which was present in heterozygosity in both unaffected parents and an unaffected sib, was not found in 189 ethnically matched controls or in the Exome Variant Server database. In coimmunoprecipitation assays, significantly lower amounts of R106P mutant POC1B than wildtype protein coprecipitated with the known retinal disease-associated protein FAM161A (613596), indicating disrupted physical interaction. Fluorescence microscopy of cotransfected hTERT-RPE1 cells showed complete loss of colocalization with FAM161A at the plasma membrane, basal body, and microtubule network; localization of the R106P mutant was cytosolic, without enrichment at specific subcellular sites. (In the article by Roosing et al. (2014), the nucleotide change for this mutation was given as c.317C-G and as c.137G-C; Cremers (2014) confirmed that the correct change is c.317G-C.)
In 4 affected members of a consanguineous Turkish family segregating autosomal recessive CORD, Durlu et al. (2014) independently identified homozygosity for the R106P missense mutation in the POC1B gene. The mutation was not found in 9 unaffected family members or in 113 population controls.
In a consanguineous Iraqi family with retinal dystrophy and other features consistent with ciliary disease, Beck et al. (2014) identified homozygosity for the R106P mutation. The proband was a 9.5-year-old boy with mental retardation who was noted to have massively enlarged polycystic kidneys (see 173900) at birth. He also had severe visual impairment, with fixation only to light and no response to visual evoked potentials. Funduscopic examination showed a small coloboma adjacent to the papilla on the right and bilateral small vessel diameters. Oculomotor apraxia as well as seesaw nystagmus typical of Joubert syndrome (see 213300) was present, and brain MRI revealed the molar tooth sign, involving cerebellar vermis hypoplasia, thick and maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. Four similarly affected children in the family had massively enlarged polycystic kidneys and died from lung hypoplasia and/or end-stage renal disease, including 2 sisters who were cousins of the proband. The sisters died at 6.5 and 9 years of age; they were also reported to have blindness, ataxia, and mental retardation. In addition, 2 affected brothers who were first cousins once removed of the proband died within the first days of life. Beck et al. (2014) performed next-generation sequencing of 125 genes, including 21 associated with Joubert syndrome, 76 with retinitis pigmentosa, 27 with Leber congenital amaurosis, and 1 with autosomal recessive PKD, but did not detect any point mutations or large structural arrangements. Genomewide linkage analysis revealed 12 regions of homozygosity by descent, and whole-exome sequencing in the proband identified 19 homozygous candidate variants within those regions. The authors focused on POC1B as the likely disease gene, and segregation analysis revealed that all 6 consanguineous parents of the affected individuals were heterozygous carriers of the R106P variant for which the proband was homozygous. Beck et al. (2014) stated that the 18 other genes in which the proband also carried at least 2 rare variants, including 5 genes with documented or likely ciliary expression, did not appear to be convincing candidates for disease in this family.
In a 55-year-old Dutch man with cone-rod dystrophy-20 (CORD20; 615973), Roosing et al. (2014) identified compound heterozygosity for a 3-bp deletion (c.199_201del) in the POC1B gene, resulting in the in-frame deletion of a moderately conserved residue (Gln67del), and a splice site mutation (c.810+1G-T; 614784.0003), both within the WD40 domain. By RT-PCR analysis of patient lymphoblasts, the splice site mutation was shown to induce skipping of exons 6 and 7 (c.561_810del; minor mutant product) or exon 7 (c.677_810del; major mutant product), predicted to result in Phe188AspfsTer73 and Val226GlyfsTer30, respectively. The patient's unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 149 ethnically matched controls or in the Exome Variant Server database. In coimmunoprecipitation assays, significantly lower amounts of Gln67del mutant POC1B than wildtype protein coprecipitated with the known retinal disease-associated protein FAM161A (613596), indicating disrupted physical interaction. Fluorescence microscopy in cotransfected hTERT-RPE1 cells showed complete loss of colocalization with FAM161A at the plasma membrane, basal body, and microtubule network; localization of the Gln67del mutant was cytosolic, without enrichment at specific subcellular sites.
For discussion of the splice site mutation in the POC1B gene (c.810+1G-T) that was found in compound heterozygous state in a patient with cone-rod dystrophy-20 (CORD20; 615973) by Roosing et al. (2014), see 614784.0002.
Beck, B. B., Phillips, J. B., Bartram, M. P., Wegner, J., Thoenes, M., Pannes, A., Sampson, J., Heller, R., Gobel, H., Koerber, F., Neugebauer, A., Hedergott, A., and 18 others. Mutation of POC1B in a severe syndromic retinal ciliopathy. Hum. Mutat. 35: 1153-1162, 2014. [PubMed: 25044745] [Full Text: https://doi.org/10.1002/humu.22618]
Cremers, F. P. M. Personal Communication. Nijmegen, The Netherlands 9/3/2014.
Durlu, Y. K., Koroglu, C., Tolun, A. Novel recessive cone-rod dystrophy caused by POC1B mutation. JAMA Ophthal. 132: 1185-1191, 2014. [PubMed: 24945461] [Full Text: https://doi.org/10.1001/jamaophthalmol.2014.1658]
Hames, R. S., Hames, R., Prosser, S. L., Euteneuer, U., Lopes, C. A. M., Moore, W., Woodland, H. R., Fry, A. M. Pix1 and Pix2 are novel WD40 microtubule-associated proteins that colocalize with mitochondria in Xenopus germ plasm and centrosomes in human cells. Exp. Cell Res. 314: 574-589, 2008. [PubMed: 18068700] [Full Text: https://doi.org/10.1016/j.yexcr.2007.10.019]
Keller, L. C., Geimer, S., Romijn, E., Yates, J., III, Zamora, I., Marshall, W. F. Molecular architecture of the centriole proteome: the conserved WD40 domain protein POC1 is required for centriole duplication and length control. Molec. Biol. Cell 20: 1150-1166, 2009. [PubMed: 19109428] [Full Text: https://doi.org/10.1091/mbc.e08-06-0619]
Pearson, C. G., Osborn, D. P., Giddings, T. H., Jr., Beales, P. L., Winey, M. Basal body stability and ciliogenesis requires the conserved component Poc1. J. Cell Biol. 187: 905-920, 2009. [PubMed: 20008567] [Full Text: https://doi.org/10.1083/jcb.200908019]
Roosing, S., Lamers, I. J. C., de Vrieze, E., van den Born, L. I., Lambertus, S., Arts, H. H., POC1B Study Group, Peters, T. A., Hoyng, C. B., Kremer, H., Hetterschijt, L., Letteboer, S. J. F., van Wijk, E., Roepman, R., den Hollander, A. I., Cremers, F. P. M. Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy. Am. J. Hum. Genet. 95: 131-142, 2014. [PubMed: 25018096] [Full Text: https://doi.org/10.1016/j.ajhg.2014.06.012]