Alternative titles; symbols
HGNC Approved Gene Symbol: PHC1
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:8,913,843-8,941,467 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | ?Microcephaly 11, primary, autosomal recessive | 615414 | Autosomal recessive | 3 |
The PHC1 gene encodes a member of the polycomb repressive complex-1 (PRC1), which maintains genes in a repressive state (summary by Awad et al., 2013).
In Drosophila melanogaster, the 'Polycomb' group (PcG) genes have been identified as repressors of gene expression. PcG proteins form a large multimeric, chromatin-associated protein complex. Nomura et al. (1994) isolated a retinoic acid-inducible mouse cDNA, designated Rae28, that encodes a protein sharing several motifs and highly homologous regions with the Drosophila PcG protein 'polyhomeotic' (Ph).
By screening a fetal brain library with an HPH2 cDNA (EDR2; 602979), Gunster et al. (1997) isolated cDNAs corresponding to the human homolog of Rae28. They called the gene HPH1 for 'human polyhomeotic homolog-1.' The amino acid sequences of HPH1 and Rae28 are 95% identical. HPH1 shares homology with HPH2 and Ph in the zinc finger domain and in 2 regions designated homology domains I and II. Northern blot analysis revealed that HPH1 was expressed as 4.4- and 6-kb transcripts in several tissues, with the highest expression in thymus, testis, and ovary.
Alkema et al. (1997) identified RAE28 and the PcG proteins MEL18 (600346), M33 (602770), and BMI1 (164831) as components of a multimeric protein complex in mouse embryos and human cells.
Based on the results of 2-hybrid analysis and immunoprecipitation, cell fractionation, and immunofluorescence studies, Gunster et al. (1997) concluded that HPH1, HPH2, and BMI1 are part of a common, multimeric protein complex.
Using a coprecipitation assay, Tomotsune et al. (1999) showed that full-length mouse Scmh1 (616396) and Rae28 interacted in vitro, similar to their Drosophila orthologs. Mutation analysis revealed that the SCM domains of Scmh1 and Rae28 mediated self-association and interactions with each other.
Using mouse fetal liver cells and transfected human cells, Ohtsubo et al. (2008) showed that Rae28 deficiency impaired ubiquitin-proteasome-mediated degradation of geminin (GMMN; 602842), an inhibitor of Cdt1 (605525), and increased geminin protein stability. Retroviral transduction experiments suggested that the resultant accumulation of geminin eliminated hematopoietic stem cell activity in Rae28-deficient mice. Using purified recombinant PRC1 reconstituted in insect cells, Ohtsubo et al. (2008) confirmed that Rae28 mediated recruitment of Scmh1, which provided an interaction domain for geminin, and demonstrated that PRC1 acted as the E3 ubiquitin ligase for geminin in vitro and in vivo. They concluded that PRC1 supports hematopoietic stem cell activity through direct regulation of geminin.
Using immunoprecipitation studies, Awad et al. (2013) found that PHC1 normally interacts with H2A (613499) and is necessary for the ubiquitination of H2A. Irradiation resulted in an increase in PHC1 binding to chromatin and an increase in ubiquitinated H2A, suggesting a role in DNA damage repair.
In 2 sibs, born of related Saudi parents, with autosomal recessive primary microcephaly-11 (MCPH11; 615414), Awad et al. (2013) identified a homozygous mutation in the PHC1 gene (L992F; 602978.0001). The mutation, which was found by homozygosity mapping combined with exome sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, and 1000 Genomes Project databases or in 199 Saudi exomes or 554 Saudi control individuals. Patient cells showed normal amounts of mutant PHC1 mRNA, but a significant reduction (about 72%) in mutant protein levels, which was shown to result from proteosome-mediated degradation. Patient cells showed increased expression of geminin and decreased interaction between PHC1 and ubiquitinated H2A (613499) compared to control cells. These changes were replicated by siRNA against PHC1. Patient cells also showed an increase in DNA damage and defective DNA repair in response to irradiation, as well as abnormal cell cycle activity consistent with reduced proliferative activity, compared to controls. These defects were associated with abnormalities in chromatin regulation, and could be rescued in patient cells by overexpression of wildtype PHC1. Gene microarray analysis of patient cells showed dysregulation of a large number of genes involved in cell cycle regulation. The findings highlighted a role for chromatin remodeling in the pathogenesis of primary microcephaly.
Martinez et al. (2009) found that Ph deletion in Drosophila caused 90% lethality. Surviving mutant adults had enlarged eyes containing an increased number of ommatidia, with overproliferation of cells into neighboring tissues and loss of the ability of cells to differentiate or polarize. The massive overproliferation of Ph mutant cells was rescued by ectopic expression of a dominant-negative form of Notch (190198) or by RNA interference-mediated repression of Notch. Conversely, overexpression of Ph induced a small-eye phenotype that was rescued by activation of Notch signaling. Martinez et al. (2009) concluded that Ph controls cellular proliferation by silencing Notch signaling.
In 2 sibs, born of related Saudi parents, with autosomal recessive primary microcephaly-11 (MCPH11; 615414), Awad et al. (2013) identified a homozygous c.2974C-T transition in the PHC1 gene, resulting in a leu992-to-phe (L992F) substitution at a conserved residue in the SAM domain important for target protein binding. The mutation, which was found by homozygosity mapping combined with exome sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, and 1000 Genomes Project databases or in 199 Saudi exomes or 554 Saudi control individuals. Patient cells showed normal amounts of mutant PHC1 mRNA, but a significant reduction (about 72%) in mutant protein levels, which was shown to result from proteosome-mediated degradation. Patient cells showed increased expression of geminin (GMNN; 602842) and decreased interaction between PHC1 and ubiquitinated H2A (613499) compared to control cells. These changes were replicated by siRNA against PHC1. Patient cells also showed an increase in DNA damage and defective DNA repair in response to irradiation, as well as abnormal cell cycle activity consistent with reduced proliferative activity, compared to controls. These defects were associated with abnormalities in chromatin regulation, and could be rescued in patient cells by overexpression of wildtype PHC1. Gene microarray analysis of patient cells showed dysregulation of a large number of genes involved in cell cycle regulation. The findings highlighted a role for chromatin remodeling in the pathogenesis of primary microcephaly.
Alkema, M. J., Bronk, M., Verhoeven, E., Otte, A., van't Veer, L. J., Berns, A., van Lohuizen, M. Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev. 11: 226-240, 1997. [PubMed: 9009205] [Full Text: https://doi.org/10.1101/gad.11.2.226]
Awad, S., Al-Dosari, M. S., Al-Yacoub, N., Colak, D., Salih, M. A., Alkuraya, F. S., Poizat, C. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum. Molec. Genet. 22: 2200-2213, 2013. [PubMed: 23418308] [Full Text: https://doi.org/10.1093/hmg/ddt072]
Gunster, M. J., Satijn, D. P. E., Hamer, K. M., den Blaauwen, J. L., de Bruijn, D., Alkema, M. J., van Lohuizen, M., van Driel, R., Otte, A. P. Identification and characterization of interactions between the vertebrate polycomb-group protein BMI1 and human homologs of polyhomeotic. Molec. Cell. Biol. 17: 2326-2335, 1997. [PubMed: 9121482] [Full Text: https://doi.org/10.1128/MCB.17.4.2326]
Martinez, A.-M., Schuettengruber, B., Sakr, S., Janic, A., Gonzalez, C., Cavalli, G. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nature Genet. 41: 1076-1082, 2009. [PubMed: 19749760] [Full Text: https://doi.org/10.1038/ng.414]
Nomura, M., Takihara, Y., Shimada, K. Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells: one of the early inducible clones encodes a novel protein sharing several highly homologous regions with a Drosophila polyhomeotic protein. Differentiation 57: 39-50, 1994. [PubMed: 8070621] [Full Text: https://doi.org/10.1046/j.1432-0436.1994.5710039.x]
Ohtsubo, M., Yasunaga, S., Ohno, Y., Tsumura, M., Okada, S., Ishikawa, N., Shirao, K., Kikuchi, A., Nishitani, H., Kobayashi, M., Takihara, Y. Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity. Proc. Nat. Acad. Sci. 105: 10396-10401, 2008. [PubMed: 18650381] [Full Text: https://doi.org/10.1073/pnas.0800672105]
Tomotsune, D., Takihara, Y., Berger, J., Duhl, D., Joo, S., Kyba, M., Shirai, M., Ohta, H., Matsuda, Y., Honda, B. M., Simon, J., Shimada, K., Brock, H. W., Randazzo, F. A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog protein, is highly conserved, and interacts with RAE28/mph1 in vitro. Differentiation 65: 229-239, 1999. [PubMed: 10653359] [Full Text: https://doi.org/10.1046/j.1432-0436.1999.6540229.x]